Endo180, an endocytic recycling glycoprotein related to the macrophage mannose receptor is expressed on fibroblasts, endothelial cells and macrophages and functions as a lectin receptor.
Endo180 was previously characterized as a novel, cell type specific, recycling transmembrane glycoprotein. This manuscript describes the isolation of a full length human Endo180 cDNA clone which was shown to encode a fourth member of a family of proteins comprising the macrophage mannose receptor, the phospholipase A(2) receptor and the DEC-205/MR6 receptor. This receptor family is unusual in that they contain 8-10 C-type lectin carbohydrate recognition domains in a single polypeptide backbone, however, only the macrophage mannose receptor had been shown to function as a lectin. Sequence analysis of Endo180 reveals that the second carbohydrate recognition domain has retained key conserved amino acids found in other functional C-type lectins. Furthermore, it is demonstrated that this protein displays Ca(2+)-dependent binding to N-acetylglucosamine but not mannose affinity columns. In order to characterize the physiological function of Endo180, a series of biochemical and morphological studies were undertaken. Endo180 is found to be predominantly expressed in vivo and in vitro on fibroblasts, endothelial cells and macrophages, and the distribution and post-translational processing in these cells is consistent with Endo180 functioning to internalize glycosylated ligands from the extracellular milieu for release in an endosomal compartment.


Effects of atrial fibrillation on long-term outcomes in patients hospitalized for heart failure in Japan: a report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).
Atrial fibrillation (AF) is a common arrhythmia in patients with heart failure (HF), but its prognostic importance is controversial. The effect of AF on long-term outcomes, including mortality and rehospitalization, among unselected HF patients hospitalized with HF in routine clinical practice in Japan was assessed in the present study. The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) prospectively studied the characteristics and treatment strategies of a broad sample of patients hospitalized with worsening HF and the outcomes were followed with an average of 2.4 years of follow-up. The study cohort (n=2,659) was grouped according to the presence (n=937; 35.2%) or absence (n=1,722; 64.8%) of AF at baseline. After multivariable adjustment, patients with and without AF had a comparable risk for all-cause death (adjusted hazard ratio (HR) 0.931, 95% confidence interval (CI) 0.690-1.258, P=0.643), cardiac death (adjusted HR 0.949, 95%CI 0.655-1.377, P=0.784), rehospitalization because of the worsening HF (adjusted HR 1.028, 95%CI 0.816-1.295, P=0.816), and all-cause death or rehospitalization (adjusted HR 1.039, 95%CI 0.842-1.281, P=0.722). Among patients hospitalized for HF in Japan, AF was common, but was not an independent risk for long-term adverse outcomes, including death or rehospitalization, in routine clinical practice.


Contrasting patterns of genetic structuring in natural populations of Arabidopsis lyrata Subsp. petraea across different regions in northern Europe.
Level and partitioning of genetic diversity is expected to vary between contrasting habitats, reflecting differences in strength of ecological and evolutionary processes. Therefore, it is necessary to consider processes acting on different time scales when trying to explain diversity patterns in different parts of species' distributions. To explore how historical and contemporary factors jointly may influence patterns of genetic diversity and population differentiation, we compared genetic composition in the perennial herb Arabidopsis lyrata ssp. petraea from the northernmost parts of its distribution range on Iceland to that previously documented in Scandinavia. Leaf tissue and soil were sampled from ten Icelandic populations of A. lyrata. Seedlings were grown from soil samples, and tissue from above-ground and seed bank individuals were genotyped with 21 microsatellite markers. Seed bank density in Icelandic populations was low but not significantly different from that observed in Norwegian populations. While within-population genetic diversity was relatively high on Iceland (H(E) = 0.35), among-population differentiation was low (F(ST) = 0.10) compared to Norwegian and Swedish populations. Population differentiation was positively associated with geographical distance in both Iceland and Scandinavia, but the strength of this relationship varied between regions. Although topography and a larger distribution range may explain the higher differentiation between mountainous Norwegian relative to lowland populations in Sweden, these factors cannot explain the lower differentiation in Icelandic compared to Swedish populations. We propose that low genetic differentiation among Icelandic populations is not caused by differences in connectivity, but is rather due to large historical effective population sizes. Thus, rather than contemporary processes, historical factors such as survival of Icelandic lineages in northern refugia during the last glacial period may have contributed to the observed pattern.


A comparison of obstetric maneuvers for the acute management of shoulder dystocia.
To assess the efficacy of obstetric maneuvers for resolving shoulder dystocia and the effect that these maneuvers have on neonatal injury when shoulder dystocia occurs. Using an electronic database encompassing 206,969 deliveries, we identified all women with a vertex fetus beyond 34 0/7 weeks of gestation who incurred a shoulder dystocia during the process of delivery. Women whose fetuses had a congenital anomaly and women with an antepartum stillbirth were excluded. Medical records of all cases were reviewed by trained abstractors. Cases involving neonatal injury (defined as brachial plexus injury, clavicular or humerus fracture, or hypoxic-ischemic encephalopathy or intrapartum neonatal death attributed to the shoulder dystocia) were compared with those without injury. Among 132,098 women who delivered a term cephalic liveborn fetus vaginally, 2,018 incurred a shoulder dystocia (1.5%), and 101 (5.2%) of these incurred a neonatal injury. Delivery of the posterior shoulder was associated with the highest rate of delivery when compared with other maneuvers (84.4% compared with 24.3-72.0% for other maneuvers; P<.005 to P<.001) and similar rates of neonatal injury (8.4% compared with 6.1-14.0%; P=.23 to P=.7). The total number of maneuvers performed significantly correlated with the rate of neonatal injury (P<.001). Delivery of the posterior shoulder should be considered following the McRoberts maneuver and suprapubic pressure in the management of shoulder dystocia. The need for additional maneuvers was associated with higher rates of neonatal injury.


Transfer of the potato plant isolates of Pectobacterium wasabiae to Pectobacterium parmentieri sp. nov.
Pectobacterium wasabiae was originally isolated from Japanese horseradish (Eutrema wasabi), but recently some Pectobacterium isolates collected from potato plants and tubers displaying blackleg and soft rot symptoms were also assigned to P. wasabiae. Here, combining genomic and phenotypical data, we re-evaluated their taxonomic position. PacBio and Illumina technologies were used to complete the genome sequences of P. wasabiae CFBP 3304T and RNS 08-42-1A. Multi-locus sequence analysis showed that the P. wasabiae strains RNS 08-42-1A, SCC3193, CFIA1002 and WPP163, which were collected from potato plant environment, constituted a separate clade from the original Japanese horseradish P. wasabiae. The taxonomic position of these strains was also supported by calculation of the in-silico DNA-DNA hybridization, genome average nucleotide indentity, alignment fraction and average nucleotide indentity values. In addition, they were phenotypically distinguished from P. wasabiae strains by producing acids from (+)-raffinose, α-d(+)-α-lactose, d(+)-galactose and (+)-melibiose but not from methyl α-d-glycopyranoside, (+)-maltose or malonic acid. The name Pectobacterium parmentieri sp. nov. is proposed for this taxon; the type strain is RNS 08-42-1AT (=CFBP 8475T=LMG 29774T).


Photosynthetic responses of three C4 grasses of different metabolic subtypes to water deficit.
C4 plants are considered to be less sensitive to drought than C3 plants because of their CO2 concentrating mechanism. The C4 grasses, Paspalum dilatatum Poiret (NADP-ME), Cynodon dactylon (L.) Pers (NAD-ME) and Zoysia japonica Steudel (PEPCK) were compared in their response to water deficit imposed by the addition of polyethylene glycol to the nutrient solution in which they were grown. The effects of drought on leaf relative water content (RWC), net photosynthesis, stomatal conductance, carboxylating enzyme activities and chlorophyll a fluorescence were investigated. In C. dactylon the RWC was more sensitive, but the photosynthetic activity was less sensitive, to water deficit than in P. dilatatum and Z. japonica. The decrease of photosynthesis in P. dilatatum under water deficit was not closely related to the activities of the carboxylating enzymes or to chlorophyll a fluorescence. However, decreased activities of ribulose 1,5-bisphosphate carboxylase/oxygenase and phosphoenolpyruvate carboxylase, in addition to decreased stomatal conductance, may have contributed to the decrease of photosynthesis with drought in C. dactylon and Z. japonica. The different responses to water deficit are discussed in relation to the natural habitats of C4 grasses.


Sex differences in heritability of sensitization to Blomia tropicalis in asthma using regression of offspring on midparent (ROMP) methods.
A genetic basis for asthma- and atopy-related quantitative traits, such as allergen-specific immunoglobulin E (IgE) levels, has been suggested by the observed familial aggregation of these traits in temperate climates. Less information is available for tropical climates, where different allergens may predominate. Sensitivity to the mite Blomia tropicalis is related to asthma in tropical climates, but heritability of B. tropicalis sensitivity and the impact of age, sex, and other environmental covariates on heritability have not been widely explored. Total and specific IgE levels were measured by immunochemiluminescent assay in 481 members of 29 Barbadian families (comprised of 340 parent-offspring trios or pairs) ascertained through two asthmatic siblings. Trait heritability was estimated using regression of offspring on mid-parent (ROMP) and pairwise correlation analysis of unadjusted IgE levels and on residual values after adjustment for covariates. Heritability of IgE levels to the major antigen of B. tropicalis (Blo t M) estimated by ROMP in 180 complete parent-offspring trios was 0.56. Heritability was consistently greater for male offspring than for female offspring. Similar sex-specific patterns were observed for specific IgE to Dermatophagoides pteronyssinus and total IgE levels and were relatively unaffected by adjustment for covariates. Pairwise correlational analyses of specific and total IgE levels showed similar results. Moderate heritability of Blo t M IgE levels was detected in these Barbadian families and was greater for sons than daughters. Adjustment for covariates had minimal impact. This suggests that future investigations of genetic determinants of IgE levels should include approaches that allow for potential sex differences in their expression.


Variable responses by southern pine beetle, Dendroctonus frontalis Zimmermann, to the pheromone component endo-brevicomin: influence of enantiomeric composition, release rate, and proximity to infestations.
The male-produced bicyclic acetal endo-brevicomin is a component of the pheromone blend that mediates colonization of host pines by the bark beetle Dendroctonus frontalis Zimmermann. Efforts to identify its behavioral function have been complicated by contrasting reports that it either enhances or reduces attraction of flying beetles. Our studies failed to support the hypothesis that this published variability is due to differences in release rate and/or the enantiomeric composition [i.e., the beetle-produced (+)-enantiomer vs. the racemate] of the endo-brevicomin used in the experiments. In trapping trials within active D. frontalis infestations, racemic and (+)-endo-brevicomin did not differ from each other in behavioral effects when tested at seven different release rates ranging from 0.005 to 3 mg/d. At the highest release rates, racemic and (+)-endo-brevicomin similarly reduced catches in traps baited with an attractant (frontalin and turpentine), but neither enhanced catches at any release rate. Furthermore, the activity of racemic endo-brevicomin baits depended on trap proximity to D. frontalis infestations. Addition of these baits to attractant-baited traps located inside active infestations reduced catches, but they enhanced catches at traps located either 100 or 200 m outside these infestations. The contrasting responses may reflect differences in host-seeking strategies by either aggregated or dispersing D. frontalis, and may be elicited by differing abundance of natural sources of semiochemicals or differing responsiveness of beetles inside vs. outside of infestations. We suspect that much of the published variability in D. frontalis responses to endo-brevicomin is attributable to differing proximity of experimental field sites to infestations.


Rotavirus excretion by village pigs in Papua New Guinea.
Cohort studies were conducted on 29 pigs from 3 villages in the Highlands of Papua New Guinea. Animals ranged in age from 9 d to 5 m old. Three hundred and twenty nine faecal samples were collected from individual pigs followed over 3 to 6 w periods, and were examined for group A rotavirus antigen by ELISA, and rotaviral genomic RNA by polyacrylamide gel electrophoresis (PAGE). Electron microscopy was also conducted on selected samples. Group A rotavirus was detected in the faeces of 16 pigs with infected individuals coming from all villages. Non-group A rotavirus resembling group C was found in faeces from pigs from 2 villages. All of the group A rotaviruses examined had the same electrophoretype and this was distinct from that of the common type infecting humans in the area at the time of the study. None of the group A positive samples reacted with monoclonal antisera specific for human group A rotaviruses of serotypes 1, 2, 3, 4, or 8. The non-group A rotaviruses also all had identical electrophoretypes. In contrast to previous findings in intensive piggeries, rotavirus infection did not occur in all young pigs and was not limited to young animals under 2 m of age. Infected pigs varied in age from 12 days to 20 weeks of age. This pattern of infection was attributed to the non-intensive husbandry situations in the villages, with less opportunity for transmission to occur than in intensive piggeries.


Iron regulatory protein-1 protects against mitoferrin-1-deficient porphyria.
Mitochondrial iron is essential for the biosynthesis of heme and iron-sulfur ([Fe-S]) clusters in mammalian cells. In developing erythrocytes, iron is imported into the mitochondria by MFRN1 (mitoferrin-1, SLC25A37). Although loss of MFRN1 in zebrafish and mice leads to profound anemia, mutant animals showed no overt signs of porphyria, suggesting that mitochondrial iron deficiency does not result in an accumulation of protoporphyrins. Here, we developed a gene trap model to provide in vitro and in vivo evidence that iron regulatory protein-1 (IRP1) inhibits protoporphyrin accumulation. Mfrn1(+/gt);Irp1(-/-) erythroid cells exhibit a significant increase in protoporphyrin levels. IRP1 attenuates protoporphyrin biosynthesis by binding to the 5'-iron response element (IRE) of alas2 mRNA, inhibiting its translation. Ectopic expression of alas2 harboring a mutant IRE, preventing IRP1 binding, in Mfrn1(gt/gt) cells mimics Irp1 deficiency. Together, our data support a model whereby impaired mitochondrial [Fe-S] cluster biogenesis in Mfrn1(gt/gt) cells results in elevated IRP1 RNA-binding that attenuates ALAS2 mRNA translation and protoporphyrin accumulation.


Neutrophil dysfunction triggers inflammatory bowel disease in G6PC3 deficiency.
The glucose-6-phosphatase catalytic subunit 3 (G6PC3) encodes a ubiquitously expressed enzyme that regulates cytoplasmic glucose availability. Loss-of-function biallelic G6PC3 mutations cause severe congenital neutropenia and a diverse spectrum of extra-hematological manifestations, among which inflammatory bowel disease (IBD) has been anecdotally reported. Neutrophil function and clinical response to granulocyte colony-stimulating factor (G-CSF) and hematopoietic stem cell transplantation (HSCT) were investigated in 4 children with G6PC3 deficiency-associated IBD. G6PC3 deficiency was associated with early-onset IBD refractory to treatment with steroids and infliximab. The symptoms of IBD progressed despite G-CSF treatment. In vitro studies on the patients' blood showed that neutrophils displayed higher levels of activation markers (CD11b, CD66b, and CD14), excessive IL-8 and reactive oxygen species, and increased apoptosis and secondary necrosis. Secondary necrosis was exaggerated after stimulation with Escherichia coli and could be partially rescued with supplemental exogenous glucose. HSCT led to normalization of neutrophil function and remission of gastrointestinal symptoms. We conclude that neutrophils in G6PC3 deficiency release pro-inflammatory mediators when exposed to gut bacteria, associated with intestinal inflammation, despite treatment with G-CSF. HSCT is an effective therapeutic option in patients with G6PC3 deficiency-associated IBD refractory to immune suppressants.


Given the Cold Shoulder: A Review of the Scientific Literature for Evidence of Reptile Sentience.
We searched a selection of the scientific literature to document evidence for, and explorations into reptile sentience. The intention of this review was to highlight; (1) to what extent reptile capability for emotions have been documented in the scientific literature; (2) to discuss the implications this evidence has for the trade in reptiles; and (3) to outline what future research is needed to maximise their captive welfare needs. We used 168 keywords associated with sentience, to search through four journal databases and one open-access journal. We recorded studies that explored sentience in reptiles and those that recognised reptile sentience in their experiments. We found that reptiles were assumed to be capable of the following emotions and states; anxiety, distress, excitement, fear, frustration, pain, stress, and suffering, in 37 articles. We also found four articles that explored and found evidence for the capacity of reptiles to feel pleasure, emotion, and anxiety. These findings show that reptiles are considered to be capable of experiencing a range of emotions and states. This has implications for how reptiles are treated in captivity, as a better understanding could help to inform a range of different operational initiatives aimed at reducing negative animal welfare impacts, including improved husbandry and consumer behaviour change programmes.


Catalytic cyclization and competitive deactivation with Ru(PR2NR'2) complexes.
The first successful use of the PR2NR'2 (1,5-R'-3,7-R-1,5-diaza-3,7-diphosphacyclooctane) ligand family toward an organic synthesis is described. The precatalysts [Ru(Cp)(PR2NBn2)(MeCN)]PF6 are active toward cyclization of 2-ethynylbenzyl alcohol at low catalyst loading and mild temperatures. Catalyst performance however is limited by both low conscription and by competitive deactivation.


Dietary antioxidants and risk of Parkinson's disease in two population-based cohorts.
A neuroprotective effect of dietary antioxidants on Parkinson's disease (PD) risk has been suggested, but epidemiological evidence is limited. To examine the associations between intake of dietary antioxidant vitamins and total antioxidant capacity and risk of PD. We prospectively assessed the relationships of dietary antioxidant vitamins C and E, ß-carotene, and total antioxidant capacity with PD risk in two population-based cohorts (38,937 women and 45,837 men). During a mean 14.9-year follow-up period, 1,329 PD cases were identified. Dietary intake of ß-carotene was associated with a lower risk of PD (hazard ratio: 0.86; 95% confidence interval: 0.78-0.95; Ptrend < 0.01 for women and hazard ratio: 0.91; 95% confidence interval: 0.84-0.99; Ptrend = 0.05 for men). An inverse association between dietary vitamin E and PD risk was found in women (hazard ratio: 0.87; 95% confidence interval: 0.79-0.96; Ptrend = 0.02). Dietary intake of vitamin C was inversely associated with PD risk in women at borderline significance (hazard ratio: 0.91; 95% confidence interval: 0.83-1.00; Ptrend = 0.04). There was no association between dietary total antioxidant capacity and PD risk in either women (hazard ratio: 0.93; 95% confidence interval: 0.84-1.02; Ptrend = 0.35) or men (hazard ratio: 1.00; 95% confidence interval: 0.93-1.07; Ptrend = 0.97). Intake of dietary vitamin E and ß-carotene was associated with a lower risk of PD. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.


Tuberculous Posterior Sclero-Uveitis with Features of Vogt-Koyanagi-Harada Uveitis: An Unusual Case.
BACKGROUND Ocular tuberculosis (TB) is a clinical entity that presents with a wide range of clinical manifestations. It is regarded as an extremely challenging condition from the point of view of diagnostic approach and calls for early diagnosis and prompt treatment, as it can potentially lead to blindness. CASE REPORT This is a case report of a 32-year-old male from southern India who has been living and working in Greece over the last 10 years and presented with 2-week history of pain and progressive visual impairment of his left eye. He underwent a thorough clinical ophthalmological examination and imaging of the fundus, and the findings were consistent with uveitis. However, the manifestations of the inflammation were complicated as they included features that could be attributed mainly to Vogt-Koyanagi-Harada (VKH) disease and tuberculous serpiginous-like uveitis. Therefore, a systemic evaluation, together with specific laboratory and paraclinical investigations, were carried out to define the etiology of the inflammation and develop an optimal therapeutic plan. Taking into account specific findings from the chest imaging, a positive purified protein derivative (PPD) skin test, and sputum cultures positive for Mycobacterium tuberculosis (MTB), we set a diagnosis of posterior sclero-uveitis and started our patient on anti-tuberculous treatment. CONCLUSIONS This case reveals an atypical manifestation of tuberculous sclero-uveitis imitating Vogt-Koyanagi-Harada disease together with a few characteristics of serpiginous-like tuberculous uveitis, emphasizing the fact that tuberculosis should always be included in the differential diagnosis of uveitis when there is no obvious underlying disease.


Differential tissue/organ-dependent expression of two sucrose- and cold-responsive genes for UDP-glucose pyrophosphorylase in Populus.
Plant UDP-glucose (UDPG) pyrophosphorylase (UGPase) is involved in the production/metabolism of UDPG, a key metabolite for sucrose and cell wall biosynthesis. Two highly similar cDNAs (UGP1 and UGP2) corresponding to UGPase were isolated from cDNA libraries of hybrid aspen (Populus tremula x tremuloides). Expression of both UGPs, as studied by DNA microarrays and EST abundance, was compared to that of three sucrose synthase genes (SUS1-3), also involved in UDPG synthesis. Generally, the UGPs had lower expression than SUS1 and SUS2 genes (especially in tension wood and cambium), with the notable exception of leaves, primary roots and flowers. Based on real-time quantitative PCR, UGP1 in root xylem, leaves and male flowers was by far the predominant transcript, while in other tissues both UGP1 and UGP2 had comparable expression. In leaves, the UGP1 gene, but not UGP2, was upregulated by light and short-term sucrose feeding. Cold treatment led to dramatic organ-specific changes in relative expression of both genes, with UGP2 being upregulated either transiently (leaves), long-term (stems) or not at all (roots), whereas UGP1 was cold-upregulated in all organs. Individual or overall UGP expression patterns only weakly correlated with UGPase activity/protein; however, UGPase activity and protein were correlated in all tissues/conditions. The data suggest that UGPs are differentially expressed at the tissue level and in response to metabolic feedback (sucrose) and cold stress, and point to a tight posttranscriptional/translational control and, possibly, distinct roles for those genes.


Risk factors for drowning and near-drowning among children in Hillsborough County, Florida.
The authors obtained data from 700 households in Hillsborough County, FL, in a telephone random survey to determine risk factors for incidents of drowning and near-drowning among children in the county. The survey was conducted from August through December 1991. A combination of forced-choice and open-ended questions was used to assess adults' drowning-related knowledge, attitudes, and prevention behaviors, as well as the incidence of and the circumstances surrounding drowning and near-drowning among children who lived in those households. The results showed that although most respondents had some knowledge of the epidemiology of drowning and near-drowning among children, deficits were noted in their knowledge of the importance of adult supervision and the recommended age at which to begin children's swimming instruction. Results showed a need for isolation fencing, that which separates a swimming pool from a house and yard. Most respondents reported that they did not know how to perform cardiopulmonary resuscitation (CPR) on an infant or child. More than 40 percent reported not knowing how to perform CPR on an adult. Respondents reported no drowning or near-drowning incidents among children of their household within the last 3 years. However, the respondents did describe water-related immersions that involved children who experienced difficulty in the water, but recovered by themselves or with the aid of a nearby person. In some instances the child's breathing pattern was altered. There were three episodes during which difficulty in breathing occurred. The respondents reported a total of nine childhood water-immersion episodes within their families, none of which had been reported to treatment facilities. Recommendations are provided for programs for prevention of childhood drowning.


Cutaneous T-cell lymphoma in sub-Saharan Africa.
The incidence and economic burden of cancer in sub-Saharan Africa is increasing, and innovative strategies are needed to improve prevention and care in this population. This article uses a case of cutaneous T-cell lymphoma in Uganda to propose guidelines for the diagnosis and treatment of this disease in resource-limited settings. These guidelines were developed from the consensus opinion of specialists at the Uganda Cancer Institute and Fred Hutchinson Cancer Research Center as part of an established collaboration. Areas for future investigation that can improve the care of patients in this region are identified.


Endonasal, supraorbital, and transorbital approaches: minimal access endoscope-assisted surgical approaches for meningiomas in the anterior and middle cranial fossae.
Minimally invasive endoscope-assisted approaches to the anterior skull base offer an alternative to traditional open craniotomies. Given the restrictive operative corridor, appropriate case selection is critical for success. In this paper, the authors present the results of three different minimal access approaches to meningiomas of the anterior and middle fossae and examine the differences in the target areas considered appropriate for each approach, as well as the outcomes, to determine whether the surgical goals were achieved. A consecutive series of the endoscopic endonasal approach (EEA), supraorbital approach (SOA), or transorbital approach (TOA) for newly diagnosed meningiomas of the anterior and middle fossa skull base between 2007 and 2022 were examined. Probabilistic heat maps were created to display the distribution of tumor volumes for each approach. Gross-total resection (GTR), extent of resection, visual and olfactory outcomes, and postoperative complications were assessed. Of 525 patients who had meningioma resection, 88 (16.7%) were included in this study. EEA was performed for planum sphenoidale and tuberculum sellae meningiomas (n = 44), SOA for olfactory groove and anterior clinoid meningiomas (n = 36), and TOA for spheno-orbital and middle fossa meningiomas (n = 8). The largest tumors were treated using SOA (mean volume 28 ± 29 cm3), followed by TOA (mean volume 10 ± 10 cm3) and EEA (mean volume 9 ± 8 cm3) (p = 0.024). Most cases (91%) were WHO grade I. GTR was achieved in 84% of patients (n = 74), which was similar to the rates for EEA (84%) and SOA (92%), but lower than that for TOA (50%) (p = 0.002), the latter attributable to spheno-orbital (GTR: 33%) not middle fossa (GTR: 100%) tumors. There were 7 (8%) CSF leaks: 5 (11%) from EEA, 1 (3%) from SOA, and 1 (13%) from TOA (p = 0.326). All resolved with lumbar drainage except for 1 EEA leak that required a reoperation. Minimally invasive approaches for anterior and middle fossa skull base meningiomas require careful case selection. GTR rates are equally high for all approaches except for spheno-orbital meningiomas, where alleviation of proptosis and not GTR is the primary goal of surgery. New anosmia was most common after EEA.


Use of condensed tannin extract from quebracho trees to reduce methane emissions from cattle.
Our objective was to determine if condensed tannin extract from quebracho trees (Schinopsis quebracho-colorado; red quebracho) could be used to reduce enteric methane emissions from cattle. The experiment was designed as a repeated 3 x 3 Latin square (4 squares) with 3 treatments (0, 1, and 2% of dietary DM as quebracho tannin extract) and 3 28-d periods. Six spayed Angus heifers (238 +/- 13.3 kg of initial BW) and 6 Angus steers (207 +/- 8.2 kg of initial BW) were each assigned to 2 squares. The measured condensed tannin content of the extract was 91%, and the basal diet contained 70% forage (DM basis). Feeding quebracho tannin extract had no effect on BW, ADG, or nutrient intakes. Furthermore, it had no effect on DM, energy, or fiber (ADF and NDF) digestibility, but apparent digestibility of CP decreased linearly (P < 0.001) by 5 and 15% with 1 and 2% quebracho tannin extract, respectively. There were no effects of quebracho tannin extract on methane emissions (g/d, g/kg of DM, % of GE intake, or % of DE intake). Feeding up to 2% of the dietary DM as quebracho tannin extract failed to reduce enteric methane emissions from growing cattle, although the protein-binding effect of the quebracho tannin extract was evident.


A proposed framework for the development and qualitative evaluation of West Nile virus models and their application to local public health decision-making.
West Nile virus (WNV) is a globally distributed mosquito-borne virus of great public health concern. The number of WNV human cases and mosquito infection patterns vary in space and time. Many statistical models have been developed to understand and predict WNV geographic and temporal dynamics. However, these modeling efforts have been disjointed with little model comparison and inconsistent validation. In this paper, we describe a framework to unify and standardize WNV modeling efforts nationwide. WNV risk, detection, or warning models for this review were solicited from active research groups working in different regions of the United States. A total of 13 models were selected and described. The spatial and temporal scales of each model were compared to guide the timing and the locations for mosquito and virus surveillance, to support mosquito vector control decisions, and to assist in conducting public health outreach campaigns at multiple scales of decision-making. Our overarching goal is to bridge the existing gap between model development, which is usually conducted as an academic exercise, and practical model applications, which occur at state, tribal, local, or territorial public health and mosquito control agency levels. The proposed model assessment and comparison framework helps clarify the value of individual models for decision-making and identifies the appropriate temporal and spatial scope of each model. This qualitative evaluation clearly identifies gaps in linking models to applied decisions and sets the stage for a quantitative comparison of models. Specifically, whereas many coarse-grained models (county resolution or greater) have been developed, the greatest need is for fine-grained, short-term planning models (m-km, days-weeks) that remain scarce. We further recommend quantifying the value of information for each decision to identify decisions that would benefit most from model input.


Clinical applications of cortisol measurements in hair.
Cortisol measurements in blood, saliva and urine are frequently used to examine the hypothalamus-pituitary-adrenal (HPA) axis in clinical practice and in research. However, cortisol levels are subject to variations due to acute stress, the diurnal rhythm and pulsatile secretion. Cortisol measurements in body fluids are not always a reflection of long-term cortisol exposure. The analysis of cortisol in scalp hair is a relatively novel method to measure cumulative cortisol exposure over months up to years. Over the past years, hair cortisol concentrations (HCC) have been examined in association with a large number of somatic and mental health conditions. HCC can be used to evaluate disturbances of the HPA axis, including Cushing's syndrome, and to evaluate hydrocortisone treatment. Using HCC, retrospective timelines of cortisol exposure can be created which can be of value in diagnosing cyclic hypercortisolism. HCC have also been shown to increase with psychological stressors, including major life events, as well as physical stressors, such as endurance exercise and shift work. Initial studies show that HCC may be increased in depression, but decreased in general anxiety disorder. In posttraumatic stress disorder, changes in HCC seem to be dependent on the type of traumatic experience and the time since traumatization. Increased hair cortisol is consistently linked to obesity, metabolic syndrome and cardiovascular disease. Potentially, HCC could form a future marker for cardiovascular risk stratification, as well as serve as a treatment target.


Ultrastructure in anterior and posterior stroma of perfused human and rabbit corneas. Relation to transparency.
The authors sought to discover whether there are differences in the degree of spatial order in the fibrillar ultrastructure between anterior and posterior stroma. Human corneas were obtained from eye bank eyes. Although they had been classified as normal, some swelling remained after 3 hours of deturgescence. Freshly excised, unswollen rabbit corneas also were used. Image analysis methods were applied to transmission electron micrographs of the anterior, middle, and posterior stroma of these corneas to determine the positions and radii of fibrils, the fraction of total area occupied by fibrils, and the fibril number density. Results were used to calculate the interference factor that appears in the direct summation of the fields for light scattering theory and to estimate the total scattering cross-section per fibril. The interference factor is a measure of the spatial order in the positions and sizes of the fibrils. Electron micrographs showed anterior-posterior variations in size and number density of fibrils. The interference factor at wavelengths of visible light was lower in posterior stroma than in anterior stroma for humans and rabbits. In some instances in humans, the anterior interference factor was characteristic of mildly swollen cornea. When averaged for the electron micrographs analyzed, the anterior stroma was predicted to scatter approximately twice as much light per unit depth as the posterior stroma in humans (at any given wavelength) and approximately three times as much in rabbits. Calculations of the interference factor showed that there were differences in the anterior-posterior spatial ordering of fibrils. In human corneas, the differences could have been caused by intrinsic in vivo differences between anterior and posterior stroma; however, possible anterior-posterior variations in swelling between the two regions in vitro also could have affected the results.


Whole-brain glutamate metabolism evaluated by steady-state kinetics using a double-isotope procedure: effects of gabapentin.
Cerebral rates of anaplerosis are known to be significant, yet the rates measured in vivo have been debated. In order to track glutamate metabolism in brain glutamatergic neurons and brain glia, for the first time unrestrained awake rats were continuously infused with a combination of H14CO3- and [1 - 13C]glucose in over 50 infusions ranging from 5 to 60 min. In whole-brain extracts from these animals, the appearance of 14C in brain glutamate and glutamine and appearance of 13C in the C-4 position of glutamate and glutamine were measured as a function of time. The rate of total neuronal glutamate turnover, the anaplerotic rate of synthesis of glutamine and glutamate from H14CO3-, flux through the glutamate/glutamine cycle, and a minimum estimate of whole-brain anaplerosis was obtained. The rate of synthesis of 14C-glutamate from H14CO3- was 1.29 +/- 0.11 nmoles/min/mg protein, whereas the rate of synthesis of 14C-glutamine was 1.48 +/- 0.10 nmoles/min/mg protein compared to total glutamate turnover of 9.39 +/- 0.73 nmoles/min/mg protein. From the turnover rate of glutamine, an upper limit for flux through the glutamate/glutamine cycle was estimated at 4.6 nmoles/min/mg protein. Synthesis of glutamine from H14CO3- was substantial, amounting to 32% of the glutamate/glutamine cycle. These rates were not significantly affected by a single injection of 100 mg/kg of the antiepileptic drug gabapentin. In contrast, acute administration of gabapentin significantly lowered incorporation of H14CO3- into glutamate and glutamine in excised rat retinas, suggesting metabolic effects of gabapentin may require chronic treatment and/or are restricted to brain areas enriched in target enzymes such as the cytosolic branched chain aminotransferase. We conclude that the brain has a high anaplerotic activity and that the combination of two tracers with different precursors affords unique insights into the compartmentation of cerebral metabolism.


Cerebrovascular autoregulation in preterm fetal growth restricted neonates.
To investigate the effect of fetal growth restriction (FGR) on cerebrovascular autoregulation in preterm neonates during the first 3 days of life. Case-control study. Neonatal intensive care unit of the Wilhelmina Children's Hospital, The Netherlands. 57 FGR (birth weight <10th percentile) and 57 appropriate for gestational age (AGA) (birth weight 20th-80th percentiles) preterm neonates, matched for gender, gestational age, respiratory and blood pressure support. The correlation between continuously measured mean arterial blood pressure and regional cerebral oxygen saturation was calculated to generate the cerebral oximetry index (COx). Mean COx was calculated for each patient for each postnatal day. The percentage of time with impaired autoregulation (COx>0.5) was also calculated. FGR neonates had higher mean COx values than their AGA peers on day 2 (0.15 (95% CI 0.11 to 0.18) vs 0.09 (95% CI 0.06 to 0.13), p=0.029) and day 3 (0.17 (95% CI 0.13 to 0.20) vs 0.09 (95% CI 0.06 to 0.12), p=0.003) of life. FGR neonates spent more time with impaired autoregulation (COx value >0.5) than controls on postnatal day 2 (19% (95% CI 16% to 22%) vs 14% (95% CI 12% to 17%), p=0.035) and day 3 (20% (95% CI 17% to 24%) vs 15% (95% CI 12% to 18%), p=0.016). FGR preterm neonates more frequently display impaired cerebrovascular autoregulation compared with AGA peers on days 2 and 3 of life which may predispose them to brain injury. Further studies are required to investigate whether this impairment persists beyond the first few days of life and whether this impairment is linked to poor neurodevelopmental outcome.


Application of redox mediators to accelerate the transformation of reactive azo dyes in anaerobic bioreactors.
Azo dyes are nonspecifically reduced under anaerobic conditions but the slow rates at which reactive azo dyes are converted presents a serious problem for the application of anaerobic technology as a first stage in the complete biodegradation of these compounds. As quinones have been found to catalyze reductive transfers by acting as redox mediators, the application of anthraquinone-2,6-disulfonic acid (AQDS) during continuous anaerobic treatment of the reactive azo dye, Reactive Red 2 (RR2), was evaluated. A mixture of volatile fatty acids was used as the electron-donating primary substrate. Batch experiments demonstrated that AQDS could increase the first-order rate constant of RR2 reductive cleavage by one order of magnitude. In the continuous experiment, treatment of RR2 containing synthetic wastewater in a lab-scale upflow anaerobic sludge blanket (UASB) reactor yielded low dye removal efficiencies (<30%). Consequently, severe toxicity problems occurred, eventually resulting in almost complete inhibition of the methanogenic activity. Addition of catalytic concentrations of AQDS (19 microM) to the reactor influent caused an immediate increase in the dye removal efficiency and recovery of biological activity. Ultimately, RR2 removal efficiency stabilized at 88%, and higher AQDS loads resulted in higher RR2 removal efficiencies (up to 98% at 155 microM AQDS). Examination of the RR2 decolorizing properties of dye-adapted reactor sludge and of nonadapted reactor seed sludge revealed that RR2 decolorization was principally a biologically driven transfer of reducing equivalents from endogenous and added substrates to the dye. Hydrogen, added in bulk, was clearly the preferred electron donor. Bacteria that couple dye decolorization to hydrogen oxidation were naturally present in seed sludge. However, enrichment was required for the utilization of electrons from volatile fatty acids for dye reduction. The stimulatory effect of AQDS on RR2 decolorization by AQDS-unadapted sludge was mainly due to assisting the electron transfer from endogenous substrates in the sludge to the dye. The stimulatory effect of AQDS on RR2 decolorization by sludge from the AQDS-exposed reactor was, in addition, strongly associated with the transfer of electrons from hydrogen and acetate to the dye, probably due to enrichment of specialized AQDS-reducing bacteria.


Driving during alcohol hangover among dutch professional truck drivers.
Alcohol hangover may impair potentially dangerous daily activities such as driving a car or operating heavy machinery. The purpose of the present study was to determine (1) whether driving during alcohol hangover is a problem of concern among professional Dutch truck drivers and (2) to what extent they think their hangover state affects driving performance. Three hundred forty-three professional truck drivers were interviewed at a Dutch trucker festival. In addition to demographics, data were gathered on normal driving, alcohol consumption and hangover, and driving style during alcohol hangover. More than half of the professional drivers who consume alcohol and report occasionally having a hangover (56.4%) acknowledge that they have driven while having a hangover during the past year: 26.5 percent only when driving private, 2.6 percent only when driving professionally, and 27.4 percent both private and professionally. Additionally, 45.3 percent reported driving while having a hangover sometimes, whereas 7.7 percent and 1.7 percent reported doing so often or always, respectively. During alcohol hangover, professional drivers rated their driving style as significantly less relaxed, less safe, and less responsible (P < .001). Driving with a hangover is a common phenomenon, and professional drivers acknowledge that their driving is impaired. Therefore, future experimental research should examine the magnitude of impairment while driving with an alcohol hangover.


The limits of checklists: handoff and narrative thinking.
Concerns about the role of communication failures in adverse events coupled with the success of checklists in addressing safety hazards have engendered a movement to apply structured tools to a wide variety of clinical communication practices. While standardised, structured approaches are appropriate for certain activities, their usefulness diminishes considerably for practices that entail constructing rich understandings of complex situations and the handling of ambiguities and unpredictable variation. Drawing on a prominent social science theory of cognition, this article distinguishes between two radically different modes of human thought, each with its own strengths and weaknesses. The paradigmatic mode organises context-free knowledge into categorical hierarchies that emphasise member-to-category relations in order to apply universal truth conditions. The narrative mode, on the other hand, organises context-sensitive knowledge into temporal plots that emphasise part-to-whole relations in order to develop meaningful, holistic understandings of particular events or identities. Both modes are crucial to human cognition but are appropriate responses for different kinds of tasks and situations. Many communication-intensive practices in which patient cases are communicated, such as handoffs, rely heavily on the narrative mode, yet most interventions assume the paradigmatic mode. Improving the safety and effectiveness of these practices, therefore, necessitates greater attention to narrative thinking.


Impact of Breast Density Legislation on Breast Cancer Risk Assessment and Supplemental Screening: A Survey of 110 Radiology Facilities.
Breast density notification laws, passed in 19 states as of October 2014, mandate that patients be informed of their breast density. The purpose of this study is to assess the impact of this legislation on radiology practices, including performance of breast cancer risk assessment and supplemental screening studies. A 20-question anonymous web-based survey was emailed to radiologists in the Society of Breast Imaging between August 2013 and March 2014. Statistical analysis was performed using Fisher's exact test. Around 121 radiologists from 110 facilities in 34 USA states and 1 Canadian site responded. About 50% (55/110) of facilities had breast density legislation, 36% of facilities (39/109) performed breast cancer risk assessment (one facility did not respond). Risk assessment was performed as a new task in response to density legislation in 40% (6/15) of facilities in states with notification laws. However, there was no significant difference in performing risk assessment between facilities in states with a law and those without (p < 0.831). In anticipation of breast density legislation, 33% (16/48), 6% (3/48), and 6% (3/48) of facilities in states with laws implemented handheld whole breast ultrasound (WBUS), automated WBUS, and tomosynthesis, respectively. The ratio of facilities offering handheld WBUS was significantly higher in states with a law than in states without (p < 0.001). In response to breast density legislation, more than 33% of facilities are offering supplemental screening with WBUS and tomosynthesis, and many are performing formal risk assessment for determining patient management.


The Adjuvant Activity of Epimedium Polysaccharide-Propolis Flavone Liposome on Enhancing Immune Responses to Inactivated Porcine Circovirus Vaccine in Mice.
Objectives. The adjuvant activity of Epimedium polysaccharide-propolis flavone liposome (EPL) was investigated in vitro and in vivo. Methods. In vitro, the effects of EPL at different concentrations on splenic lymphocytes proliferation and mRNA expression of IFN-γ and IL-6 were determined. In vivo, the adjuvant activities of EPL, EP, and mineral oil were compared in BALB/c mice through vaccination with inactivated porcine circovirus type 2 (PCV2) vaccine. Results. In vitro, EPL promoted lymphocytes proliferation and increased the mRNA expression of IFN-γ and IL-6, and the effect was significantly better than EP at all concentrations. In vivo, EPL significantly promoted the lymphocytes proliferation and the secretion of cytokines and improved the killing activity of NK cells, PCV2-specific antibody titers, and the proportion of T-cell subgroups. The effects of EPL were significantly better than EP and oil adjuvant at most time points. Conclusion. EPL could significantly improve both PCV2-specific cellular and humoral immune responses, and its medium dose had the best efficacy. Therefore, EPL would be exploited in an effective immune adjuvant for inactivated PCV2 vaccine.


Curiously modern DNA for a "250 million-year-old" bacterium.
Studies of ancient DNA have attracted considerable attention in scientific journals and the popular press. Several of the more extreme claims for ancient DNA have been questioned on biochemical grounds (i.e., DNA surviving longer than expected) and evolutionary grounds (i.e., nucleotide substitution patterns not matching theoretical expectations for ancient DNA). A recent letter to Nature from Vreeland et al. (2000), however, tops all others with respect to age and condition of the specimen. These researchers extracted and cultured a bacterium from an inclusion body from what they claim is a 250 million-year (Myr)-old salt crystal. If substantiated, this observation could fundamentally alter views about bacterial physiology, ecology and evolution. Here we report on molecular evolutionary analyses of the 16S rDNA from this specimen. We find that 2-9-3 differs from a modern halophile, Salibacillus marismortui, by just 3 unambiguous bp in 16S rDNA, versus the approximately 59 bp that would be expected if these bacteria evolved at the same rate as other bacteria. We show, using a Poisson distribution, that unless it can be shown that S. marismortui evolves 5 to 10 times more slowly than other bacteria for which 16S rDNA substitution rates have been established, Vreeland et al.'s claim would be rejected at the 0.05 level. Also, a molecular clock test and a relative rates test fail to substantiate Vreeland et al.'s claim that strain 2-9-3 is a 250-Myr-old bacterium. The report of Vreeland et al. thus falls into a long series of suspect ancient DNA studies.


Meis1 regulates epidermal stem cells and is required for skin tumorigenesis.
Previous studies have shown that Meis1 plays an important role in blood development and vascular homeostasis, and can induce blood cancers, such as leukemia. However, its role in epithelia remains largely unknown. Here, we uncover two roles for Meis1 in the epidermis: as a critical regulator of epidermal homeostasis in normal tissues and as a proto-oncogenic factor in neoplastic tissues. In normal epidermis, we show that Meis1 is predominantly expressed in the bulge region of the hair follicles where multipotent adult stem cells reside, and that the number of these stem cells is reduced when Meis1 is deleted in the epidermal tissue of mice. Mice with epidermal deletion of Meis1 developed significantly fewer DMBA/TPA-induced benign and malignant tumors compared with wild-type mice, suggesting that Meis1 plays a role in both tumor development and malignant progression. This is consistent with the observation that Meis1 expression increases as tumors progress from benign papillomas to malignant carcinomas. Interestingly, we found that Meis1 localization was altered to neoplasia development. Instead of being localized to the stem cell region, Meis1 is localized to more differentiated cells in tumor tissues. These findings suggest that, during the transformation from normal to neoplastic tissues, a functional switch occurs in Meis1.


On the resistance to extinction of fear conditioned to angry faces.
The present study investigated whether, like fear conditioned to pictures of snakes and spiders, fear conditioned to angry faces resists extinction even after verbal instruction and removal of the shock electrode. Participants were trained in a differential Pavlovian fear conditioning procedure with angry face or happy face conditional stimuli (CSs). Prior to extinction, half the participants in each group were informed that no more unconditional stimuli would be presented and the shock electrode was removed. In the absence of this manipulation, participants showed resistance to extinction after training with angry face CSs, but not after training with happy face CSs. Instructed extinction and electrode removal abolished fear conditioning regardless of the emotion expressed by the CS faces. This finding suggests that fear conditioned to angry faces, like fear conditioned to racial out-group faces, is more malleable than fear conditioned to snakes and spiders.


Effects of Competitive Triathlon Training on Telomere Length.
Telomeres act as a mitotic clock and telomere-related senescence has been linked to age-related physiological decline. There is increasing evidence lifestyle factors can influence telomere length (TL). The purpose of this study was to determine the effect of competitive triathlon training on TL. Seven competitive male triathletes and seven recreationally active males participated in the study. Relative TL was measured using quantitative polymerase chain reaction. Physiological parameters key to athletic performance such as maximal oxygen intake, lactate threshold, and running economy were also measured. Triathletes had longer telomeres than the recreationally active (1.257 ± 0.028 vs. 1.002 ± 0.014; p < .0001). Positive association was found between TL and maximal oxygen intake, lactate threshold, and running economy (R2 = .677, .683, and .696, respectively). This study indicates that competitive triathlon training buffers against age-related telomere shortening, and there is a correlation between exercise behaviors, higher maximal oxygen intake, and TL.


Group psychotherapy reduces illness intrusiveness in systemic lupus erythematosus.
We investigated whether brief supportive-expressive group psychotherapy might reduce illness-induced interference with valued activities and interests (i.e., illness intrusiveness) among women with systemic lupus erythematosus (SLE) in relation to 3 life domains: (1) relationships and personal development (family relationships, other social relationships, self-expression), (2) intimacy (relationship with spouse, sex life), and/or (3) instrumental life (work, finances, active recreation). Women with SLE recruited from 9 rheumatology centers were randomly assigned to receive either usual care (n = 66) or a 12 week brief supportive-expressive group psychotherapy followed by 3 monthly booster sessions (n = 58). Standard instruments assessed disease activity and damage, illness intrusiveness, and psychological distress at 4 measurement occasions: (1) pretreatment, (2) posttreatment, (3) 6 month followup, and (4) 12 month followup. Analysis of covariance, controlling for disease activity and household income, indicated that women who received brief supportive-expressive group psychotherapy experienced significant reductions in illness intrusiveness for 2 of 3 domains: (1) relationships and personal development and (2) intimacy. Benefits were evident at 6 and 12 month followups. Brief supportive-expressive group psychotherapy facilitates adaptation to SLE by assisting women in reducing illness-induced disruptions into important domains of life experience.


Antigenic epitopes on the outer membrane protein A of Escherichia coli identified with single-chain variable fragment (scFv) antibodies.
Bacterial meningitis is a severe disease that is fatal to one-third of patients. The major cause of meningitis in neonates is Escherichia coli (E. coli) K1. This bacterium synthesizes an outer membrane protein A (OmpA) that is responsible for the adhesion to (and invasion of) endothelial cells. Thus, the OmpA protein represents a potential target for developing diagnostic and therapeutic agents for meningitis. In this study, we expressed recombinant OmpA proteins with various molecular weights in E. coli. The sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) was performed to check the molecular size of OmpA's full length (FL) and truncated proteins. OmpA-FL protein was purified for immunizing chickens to produce immunoglobulin yolk (IgY) antibodies. We applied phage display technology to construct antibody libraries (OmpA-FL scFv-S 1.1 × 107 and OmpA-FL scFv-L 5.01 × 106) to select specific anti-OmpA-FL scFv antibodies; these were characterized by their binding ability to recombinant or endogenous OmpA using ELISA, immunofluorescent staining, and confirmed with immunoblotting. We found 12 monoclonal antibodies that react to OmpA fragments; seven scFvs recognize fragments spanning amino acid (aa) residues 1-346, aa 1-287, aa 1-167, and aa 60-192, while five scFvs recognize fragments spanning aa 1-346 and aa 1-287 only. Two fragments (aa 246-346 and aa 287-346) were not recognized with any of the 12 scFvs. Together, the data suggest three antigenic epitopes (60 aa-160 aa, 161 aa-167 aa, 193 aa-245 aa) recognized by monoclonal antibodies. These scFv antibodies show strong reactivity against OmpA proteins. We believe that antibodies show promising diagnostic agents for E. coli K1 meningitis.


MiRNA-196 is upregulated in glioblastoma but not in anaplastic astrocytoma and has prognostic significance.
MicroRNAs (miRNA) are short noncoding RNAs that can play critical roles in diverse biological processes. They are implicated in tumorigenesis and function both as tumor suppressors and as oncogenes. The clinical significance of miRNA expression profiles in malignant gliomas remains unclear. In this study, we examined the expression levels of 365 mature human miRNAs in 12 malignant gliomas, including 8 glioblastomas and 4 anaplastic astrocytomas, using TaqMan real-time quantitative PCR arrays. A validation study was done to corroborate a subset of the results, including expression levels of miR-196a, -196b, -21, and -15b, by analyzing 92 malignant gliomas by conventional real-time PCR. We modeled the relationship between the expression levels of these miRNAs and the survival rate of 39 glioblastoma patients by Kaplan-Meier method and multivariate analysis. Expression profiles in glioblastomas and anaplastic astrocytomas suggested that 16 miRNAs were candidate markers associated with the malignant progression of gliomas. Among them, miR-196a showed the most significant difference (P = 0.0038), with miR-196b also having a high significance (P = 0.0371). Both miRNAs showed increased expression levels in glioblastomas relative to both anaplastic astrocytomas and normal brains in the validation study. Furthermore, patients with high miR-196 expression levels showed significantly poorer survival by the Kaplan-Meier method (P = 0.0073). Multivariate analysis showed that miR-196 expression levels were an independent predictor of overall survival in all 39 glioblastoma patients (P = 0.021; hazard ratio, 2.81). Our results suggest that miR-196 may play a role in the malignant progression of gliomas and may be a prognostic predictor in glioblastomas.


Evaluation of the Sydney "Quit. For Life" anti-smoking campaign. Part 1. Achievement of intermediate goals.
The "Quit. For Life" campaign was a media-based programme that was aimed at reducing the prevalence of smoking in Sydney. The programme committee set four intermediate goals which it felt had to be met for such a change in prevalence to occur. From households selected at random in Sydney and Melbourne, 5713 people were interviewed to assess whether the campaign attained these goals. The television commercials that were designed for the campaign, their frequency and the timing of their screening produced a higher recall of the commercial's message and the use of campaign back-up services than were specified originally in the goals. During the campaign there was a progressive increase in the number of smokers in Sydney who reported that they were likely to quit; this was significantly different from Melbourne data by the end of the campaign and thus fulfilled another campaign goal. However, shortly after the campaign ended, the proportion of smokers who intended to quit smoking was the same in the two cities. A cohort study of 949 people from the baseline study showed that, during the 12-month period of follow-up, 66% of Sydney smokers tried to stop or to reduce their smoking. In the control city, Melbourne, 60% of smokers reported making such attempts. Of the original smokers, 23% in Sydney and 9% in Melbourne quit during the follow-up period--a statistically significant difference. As well, 10% of the original ex-smokers in Sydney and 11% in Melbourne relapsed, while 4% of nonsmokers in both cities began smoking by the end of the second survey.


The meaning of women's experience of living with long-term urinary incontinence is powerlessness.
The aim was to illuminate the meaning of women's experiences of living with urinary incontinence (UI). Living with long-term UI means a variety of consequences for everyday life. Women's narratives about their lived experiences are important in enabling nurses to better understand and to help women achieve symptom control. No previous study could be found that has focused on the meaning of women's experience of living with UI from a symptom management perspective. Fourteen women with UI (range: 34-52 years) who had sought professional help were interviewed. A phenomenological hermeneutic method was used to analyse and interpret the interview texts. The women's experiences of living with UI are presented in terms of two interlaced themes of being in a vulnerable situation and striving for adjustment. Being in a vulnerable situation means that the women had no control over UI and experienced powerlessness. The sub-themes in this case were living with an uncontrolled body, living with incontinence as taboo and experiencing a less satisfying encounter. Striving for adjustment means that the women tried to handle their incontinence in different ways to regain power and continue to live as normal. The sub-themes here were living in readiness, making urine leakage comprehensible, accepting living with UI and being familiar with the situation. Conclusion. The meaning of women's experience of living with UI is powerlessness. Nurses should supervise women in pelvic floor muscle training to achieve control over incontinence, thereby helping them regain power. Additionally, Integrated Approach to Symptom Management can help nurses enhance women's self-care abilities.


Cost effectiveness of alternative planned places of birth in woman at low risk of complications: evidence from the Birthplace in England national prospective cohort study.
To estimate the cost effectiveness of alternative planned places of birth. Economic evaluation with individual level data from the Birthplace national prospective cohort study. 142 of 147 trusts providing home birth services, 53 of 56 freestanding midwifery units, 43 of 51 alongside midwifery units, and a random sample of 36 of 180 obstetric units, stratified by unit size and geographical region, in England, over varying periods of time within the study period 1 April 2008 to 30 April 2010. 64,538 women at low risk of complications before the onset of labour. Planned birth in four alternative settings: at home, in freestanding midwifery units, in alongside midwifery units, and in obstetric units. Incremental cost per adverse perinatal outcome avoided, adverse maternal morbidity avoided, and additional normal birth. The non-parametric bootstrap method was used to generate net monetary benefits and construct cost effectiveness acceptability curves at alternative thresholds for cost effectiveness. The total unadjusted mean costs were £1066, £1435, £1461, and £1631 for births planned at home, in freestanding midwifery units, in alongside midwifery units, and in obstetric units, respectively (equivalent to about €1274, $1701; €1715, $2290; €1747, $2332; and €1950, $2603). Overall, and for multiparous women, planned birth at home generated the greatest mean net benefit with a 100% probability of being the optimal setting across all thresholds of cost effectiveness when perinatal outcomes were considered. There was, however, an increased incidence of adverse perinatal outcome associated with planned birth at home in nulliparous low risk women, resulting in the probability of it being the most cost effective option at a cost effectiveness threshold of £20 000 declining to 0.63. With regards to maternal outcomes in nulliparous and multiparous women, planned birth at home generated the greatest mean net benefit with a 100% probability of being the optimal setting across all thresholds of cost effectiveness. For multiparous women at low risk of complications, planned birth at home was the most cost effective option. For nulliparous low risk women, planned birth at home is still likely to be the most cost effective option but is associated with an increase in adverse perinatal outcomes.


Serum cholesterol and statin use predict virological response to peginterferon and ribavirin therapy.
Elevated low-density lipoprotein (LDL) levels and statin use have been associated with higher sustained virological response (SVR) rates in patients receiving chronic hepatitis C therapy. However, these relationships have not been well characterized in randomized controlled trials. Furthermore, little is known about the relationship between high-density lipoprotein (HDL) and virological response. To determine whether baseline LDL or HDL levels and statin use affect SVR rates, we retrospectively evaluated the IDEAL (Individualized Dosing Efficacy Versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy) trial, in which 3070 treatment-naive, hepatitis C virus (HCV) genotype 1-infected patients were treated for up to 48 weeks in one of the following arms: (1) peginterferon (PEG-IFN) alfa-2b at 1.5 microg/kg/week with ribavirin (RBV) at 800 to 1400 mg/day, (2) PEG-IFN alfa-2b at 1.0 microg/kg/week with RBV at 800 to 1400 mg/day, or (3) PEG-IFN alfa-2a at 180 microg/week with RBV at 1000 to 1200 mg/day. Virological responses were assessed by pretreatment statin use and baseline elevated LDL levels (> or =130 mg/dL) or low HDL levels (<40 mg/dL for men and <50 mg/dL for women). In 1464 patients with baseline elevated LDL levels or low HDL levels, the SVR rate was significantly higher than that in patients with normal levels (44.9% versus 34.0%, P < 0.001). In 66 patients receiving a statin pretreatment, the SVR rate was higher than the rate of those not receiving it (53.0% versus 39.3%, P = 0.02). In a multivariate logistic regression analysis using the stepwise selection method with baseline characteristics, a high LDL level [odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.4-1.8, P < 0.001], a low HDL level (OR = 0.5, 95% CI = 0.3-0.8, P = 0.004), and statin use (OR = 2.0, 95% CI = 1.1-3.7, P = 0.02) were independently associated with SVR. Baseline elevated LDL levels or low HDL levels and preemptive statin usage were associated with higher SVR rates. Prospective studies may be considered to explore the biological impact of these factors on HCV RNA replication and treatment response.


Zinc: A complementary factor in the treatment of chronic hepatitis C? (Review).
Chronic hepatitis C (HCV) infection persists in more than 170 million people worldwide and is one of the major causes of hepatic failure and liver transplantation. Current treatment of chronic HCV, consisting of pegylated interferon and ribavirin, is associated with a wide range of side effects, contraindications and costs, and leads to viral clearance in only 50-55% (genotype 1) to 80% (genotype 3) of cases. Thus, the development of more efficient treatment regimes with fewer side effects and costs is of high priority. It is generally accepted that the cellular immune response plays the most important role in determining the outcome of HCV infection. Moreover, oxidative stress is considered to be an important pathogenic factor. Zinc is an essential nutrient for a broad range of biological activities. It is necessary for normal liver function, and vice versa the liver plays a central role in zinc homeostasis. Zinc ions are crucial for multiple aspects of the immune system, including the normal development, differentiation and function of cells belonging to both innate and acquired immunity. Among the immune cells that are affected by zinc deficiency, T lymphocytes are noted to have the highest susceptibility. Zinc deficiency causes substantial impairment of cellular immunity, oxidation and damage to DNA. Several studies have investigated the effect of zinc supplementation in chronic HCV patients. Following zinc supplementation, decreases in the incidence of gastrointestinal disturbances, body weight loss and hair loss were found in patients with chronic HCV, along with improved fingernail health. In addition, zinc administered in combination with IFN-α was more effective against chronic HCV than treatment with IFN-α alone. Finally, in addition to the effects of zinc on immune functions and viral defence, its role as an antioxidant may be important in HCV. To conclude, the controlled application of zinc, particularly in a deficient state, is recommended as a complementary therapy for chronic hepatitis C.


Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: a double-blind randomized multicentre trial with venographic assessment. ENOXACAN Study Group.
Surgery for malignant disease carries a high risk of deep vein thrombosis. The aim of this study was to evaluate the prophylactic effect of a low molecular weight heparin, enoxaparin, 40 mg once daily, beginning 2 h before surgery, compared with that of unfractionated low-dose heparin three times daily. Patients included were over 40 years of age and undergoing planned elective curative abdominal or pelvic surgery for cancer. The study was designed as a prospective double-blind randomized multicentre trial with participating departments from ten countries. Primary outcome was venous thromboembolism as detected by mandatory bilateral venography or pulmonary scintigraphy. Follow-up was at 3 months. Some 1115 patients were randomized into the study but venograms were inadequate in 460 (41.3 per cent). Of 631 evaluable patients, a total of 104 (16.5 per cent) developed thromboembolic complications. The frequency was 18.2 per cent in the heparin group and 14.7 per cent in the enoxaparin group (95 per cent confidence interval of the difference -9.2-2.3 per cent). There were no differences in bleeding events or other complications. One patient in the heparin group developed severe thrombocytopenia. There were no differences in mortality at either 30 days or 3 months. Enoxaparin, 40 mg once daily, is as safe and effective as unfractionated heparin three times daily in preventing venous thromboembolism in patients undergoing major elective surgery for abdominal or pelvic malignancy.


Off-site control of repolarization alternans in cardiac fibers.
Repolarization alternans, a beat-to-beat alternation in action potential duration, has been putatively linked to the onset of cardiac reentry. Anti-alternans control strategies can eliminate alternans in individual cells by exploiting the rate dependence of action potential duration. The same approach, when applied to a common measuring/stimulating site at one end of a cardiac fiber, has been shown to have limited spatial efficacy. As a first step toward spatially distributed electrode control systems, we investigated "off-site" control in canine Purkinje fibers, in which the recording and control sites are different. We found experimentally that alternans can be eliminated at, or very near, the recording site, and that varying the location of the recording site along the fiber causes the node (the location with no alternans) to move along the fiber in close proximity to the recording site. Theoretical predictions based on an amplitude equation [B. Echebarria and A. Karma, Chaos 12, 923 (2002)] show that those findings follow directly from the wave nature of alternans: the most unstable mode of alternans along the fiber is a wave solution of a one-dimensional Helmholtz equation with a node position that only deviates slightly from the recording site by an amount dependent on electrotonic coupling. Computer simulations using a Purkinje fiber model confirm these theoretical and experimental results. Although off-site alternans control does not suppress alternans along the entire fiber, our results indicate that placing the node away from the stimulus site reduces alternans amplitude along the fiber, and may therefore have implications for antiarrhythmic strategies based on alternans termination.


Inclusion of an informant yields strong associations between cognitive complaint and longitudinal cognitive outcomes in non-demented elders.
The relation between the source of cognitive complaint and objective cognitive performance is not well understood. Examine self and informant cognitive complaint as predictors of objective cognitive and functional trajectory in non-demented elders. Participants from the National Alzheimer's Coordinating Center had a baseline diagnosis of normal cognition (NC; n = 6133, 72±8 years, 68% female) or mild cognitive impairment (MCI; n = 3010, 74±8 years, 55% female). Four independent groups defined cognitive complaint: no complaint, self-only complaint, informant-only complaint, or mutual complaint (both self and informant complaint). Linear mixed model regression analyses related complaint status (referent was no complaint) to cognitive and functional trajectories, adjusting for age, sex, race, education, and follow-up period. Among NC participants, mutual complaint related to faster decline in global cognition (p < 0.0001), language (all p-values <0.0001), processing speed (p = 0.0002), and executive functioning (p = 0.0006). Informant-only complaint related to faster decline in global cognition (p = 0.0001) and processing speed (p = 0.0001). Self-only complaint related to greater decline in immediate (p < 0.0001) and delayed (p = 0.0005) episodic memory. In MCI, mutual complaint related to faster decline in global cognition (p < 0.0001), verbal episodic memory (all p-values <0.0001), language (all p-values <0.0001), and processing speed(all p-values <0.0006). Informant-only or self-only complaint associations with cognitive trajectory did not survive correction factor for multiple comparisons.Conclusion: Cognitive complaint appears to have clinical significance, as it is related to declines in objective cognitive performance over time. Mutual complaint was associated with the worst cognitive trajectory in both NC and MCI elders, highlighting the importance of incorporating an informant into evaluation of elders whenever feasible.


Comparative evaluation of antimicrobial activity of hydroalcoholic extract of Aloe vera, garlic, and 5% sodium hypochlorite as root canal irrigants against Enterococcus faecalis: An in vitro study.
Enterococcus faecalis are the most resistant and predominant microorganisms recovered from root canals of teeth where previous treatment has failed. Over the past decade, interest in drugs derived from medicinal plants has markedly increased. In dentistry, phytomedicines has been used as an anti-inflammatory, antibiotic, analgesic, sedative, and also as an endodontic irrigant. In endodontics, because of the cytotoxic reactions of most of the commercial intracanal medicaments and their inability to eliminate bacteria completely from dentinal tubules, the trend is shifting toward use of biologic medication extracted from natural plants. To compare the antimicrobial efficacy of newer irrigating agents which would probably be as effective or more and at the same time less irritating to the tissues than sodium hypochlorite (NaOCl). The objective of this study was to compare the antimicrobial activity of saturated and diluted (1:1) hydroalcoholic extract of Aloe vera, garlic, and 5% NaOCl against E. faecalis using the commonly used agar diffusion method. Saturated hydroalcoholic extract of A. vera showed the highest zone of inhibition against E. faecalis. NaOCl, which is considered as gold standard, also showed higher zones of inhibition.


Simulating trait evolution for cross-cultural comparison.
Cross-cultural anthropologists have increasingly used phylogenetic methods to study cultural variation. Because cultural behaviours can be transmitted horizontally among socially defined groups, however, it is important to assess whether phylogeny-based methods--which were developed to study vertically transmitted traits among biological taxa--are appropriate for studying group-level cultural variation. Here, we describe a spatially explicit simulation model that can be used to generate data with known degrees of horizontal donation. We review previous results from this model showing that horizontal transmission increases the type I error rate of phylogenetically independent contrasts in studies of correlated evolution. These conclusions apply to cases in which two traits are transmitted as a pair, but horizontal transmission may be less problematic when traits are unlinked. We also use the simulation model to investigate whether measures of homology (the consistency index and the retention index) can detect horizontal transmission of cultural traits. Higher rates of evolutionary change have a stronger depressive impact on measures of homology than higher rates of horizontal transmission; thus, low consistency or retention indices are not necessarily indicative of 'ethnogenesis'. Collectively, these studies demonstrate the importance of using simulations to assess the validity of methods in cross-cultural research.


Ceftriaxone prevents and reverses behavioral and neuronal deficits in an MPTP-induced animal model of Parkinson's disease dementia.
Glutamatergic hyperactivity plays an important role in the pathophysiology of Parkinson's disease (PD). Ceftriaxone increases expression of glutamate transporter 1 (GLT-1) and affords neuroprotection. This study was aimed at clarifying whether ceftriaxone prevented, or reversed, behavioral and neuronal deficits in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. Male Wistar rats were injected daily with either ceftriaxone starting 5 days before or 3 days after MPTP lesioning (day 0) or saline and underwent a bar-test on days 1-7, a T-maze test on days 9-11, and an object recognition test on days 12-14, then the brains were taken for histological evaluation on day 15. Dopaminergic degeneration in the substantia nigra pars compacta and striatum was observed on days 3 and 15. Motor dysfunction in the bar test was observed on day 1, but disappeared by day 7. In addition, lesioning resulted in deficits in working memory in the T-maze test and in object recognition in the object recognition task, but these were not observed in rats treated pre- or post-lesioning with ceftriaxone. Lesioning also caused neurodegeneration in the hippocampal CA1 area and induced glutamatergic hyperactivity in the subthalamic nucleus, and both changes were suppressed by ceftriaxone. Increased GLT-1 expression and its co-localization with astrocytes were observed in the striatum and hippocampus in the ceftriaxone-treated animals. To our knowledge, this is the first study showing a relationship between ceftriaxone-induced GLT-1 expression, neuroprotection, and improved cognition in a PD rat model. Ceftriaxone may have clinical potential for the prevention and treatment of dementia associated with PD.


Correlation between epithelial cell permeability of cephalexin and expression of intestinal oligopeptide transporter.
The proton-coupled oligopeptide transporter (PEPT1) has been shown to mediate mucosal cell transport of di- and tripeptide, and some peptidomimetic drugs. In this study, we determined the correlation between PEPT1 protein expression and the permeability of cephalexin, a substrate of PEPT1, in human PEPT1 (hPEPT1)-overexpressed Caco-2 cells (Caco-2/hPEPT1 cells) and rat jejunum. Caco-2/hPEPT1 cells with various levels of hPEPT1 expression were established by an adenoviral transfection system. The effective intestinal permeability (P(eff)) in rat jejunum was evaluated using a single pass in situ perfusion method. The level of PEPT1 in Caco-2/hPEPT1 cells and rat intestinal mucosal samples was quantitated by densitometry after immunoblotting and enhanced chemiluminescence detection. In Caco-2/hPEPT1 cells, an excellent correlation was observed between cephalexin uptake and hPEPT1 expression (R2 = 0.96, P < 0.005). This demonstrates that cephalexin uptake is directly proportional to hPEPT1 expression. In the rat perfusion study, the mean P(eff) +/- S.D. (n = 15) of cephalexin was 3.89 +/- 1.63 x 10(-5) cm/s. A very significant correlation between PEPT1 expression and cephalexin permeability with an R2 = 0.63 (P < 0.001) was observed. This indicates that the variation in PEPT1 expression is one of the major factors accounting for variable intestinal cephalexin absorption. To our knowledge, this is the most direct evidence that variation of PEPT1 expression is correlated with absorption permeability variation of peptide-like compounds in vitro and in vivo.


Small-ventricle neuroendoscopy for pediatric brain tumor management.
The use of intraventricular endoscopy to achieve diagnosis or to resect accessible intraventricular or paraventricular tumors has been described in the literature in both adults and children. Traditionally, these techniques have not been used in patients with small ventricles due to the perceived risk of greater morbidity. The authors review their experience with the effectiveness and safety of endoscopic brain tumor management in children with small ventricles. Between July 2002 and December 2009, 24 children with endoscopically managed brain tumors were identified. Radiological images were reviewed by a radiologist blinded to study goals and clinical setting. Patients were categorized into small-ventricle and ventriculomegaly groups based on frontal and occipital horn ratio. Surgical success was defined a priori and analyzed between groups. Trends were identified in selected subgroups, including complications related to pathological diagnosis and surgeon experience. Six children had small ventricles and 18 had ventriculomegaly. The ability to accomplish surgical goals was statistically equivalent in children with small ventricles and those with ventriculomegaly (83% vs 89%, respectively, p = 1.00). There were no complications in the small-ventricle cohort, but in the ventriculomegaly cohort there were 2 cases of postoperative hemorrhages and 1 case of infection. All hemorrhagic complications occurred in patients with high-grade tumor histopathological type and were early in the surgeon's endoscopic career. Based on our experience, endoscopy should not be withheld in children with intraventricular tumors and small ventricles. Complications appear to be more dependent on tumor histopathological type and surgeon experience than ventricular size.


The construction of risk prediction models using GWAS data and its application to a type 2 diabetes prospective cohort.
Recent genome-wide association studies (GWAS) have identified several novel single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2D). Various models using clinical and/or genetic risk factors have been developed for T2D risk prediction. However, analysis considering algorithms for genetic risk factor detection and regression methods for model construction in combination with interactions of risk factors has not been investigated. Here, using genotype data of 7,360 Japanese individuals, we investigated risk prediction models, considering the algorithms, regression methods and interactions. The best model identified was based on a Bayes factor approach and the lasso method. Using nine SNPs and clinical factors, this method achieved an area under a receiver operating characteristic curve (AUC) of 0.8057 on an independent test set. With the addition of a pair of interaction factors, the model was further improved (p-value 0.0011, AUC 0.8085). Application of our model to prospective cohort data showed significantly better outcome in disease-free survival, according to the log-rank trend test comparing Kaplan-Meier survival curves (p--value 2:09 x 10(-11)). While the major contribution was from clinical factors rather than the genetic factors, consideration of genetic risk factors contributed to an observable, though small, increase in predictive ability. This is the first report to apply risk prediction models constructed from GWAS data to a T2D prospective cohort. Our study shows our model to be effective in prospective prediction and has the potential to contribute to practical clinical use in T2D.


Sedentary Behaviour and 12 Sleep Problem Indicators among Middle-Aged and Elderly Adults in South Africa.
The aim of this investigation was to assess the association of sedentary behaviour with 12 different sleep problem indicators among rural middle-aged and elderly adults in South Africa. Cross-sectional data were analysed from the "Health and Aging in Africa: A Longitudinal Study of an INDEPTH community in South Africa" (HAALSI) baseline survey. Participants responded to a questionnaire, including sociodemographic, health, anthropometric measures, sedentary behaviour and 12 different sleep problem indicators. The sample included 4782 individuals 40 years and older (median 61 years, interquartile range = 20 years). Overall, participants engaged <4 h (55.9%), 4-<8 h (34.1%), 8 or more hours a day (9.9%) sedentary time a day. In adjusted multinomial logistic regression, 8 h of more sedentary time was associated with short and long sleep. In adjusted logistic regression analysis, high sedentary time was positively associated with snoring, gasping, breathing stops and restless sleep and negatively associated with insufficient sleep and sleep problems due to a traumatic event. In combined analysis, compared to persons with low or moderate sedentary behaviour and moderate or high physical activity, persons with high sedentary behaviour and low physical activity were more likely to have long sleep, insufficient sleep, snoring, gasping, breathing stops, and restless sleep and less likely to have sleep problems due to traumatic events. Findings show an association between sedentary behaviour and/or combined sedentary behaviour and low physical activity with seven of 12 sleep problem indicators (short sleep, long sleep, insufficient sleep, snoring, gasping, breathing stops, and restless sleep).


G-tract RNA removes Polycomb repressive complex 2 from genes.
Polycomb repressive complex 2 (PRC2) maintains repression of cell-type-specific genes but also associates with genes ectopically in cancer. While it is currently unknown how PRC2 is removed from genes, such knowledge would be useful for the targeted reversal of deleterious PRC2 recruitment events. Here, we show that G-tract RNA specifically removes PRC2 from genes in human and mouse cells. PRC2 preferentially binds G tracts within nascent precursor mRNA (pre-mRNA), especially within predicted G-quadruplex structures. G-quadruplex RNA evicts the PRC2 catalytic core from the substrate nucleosome. In cells, PRC2 transfers from chromatin to pre-mRNA upon gene activation, and chromatin-associated G-tract RNA removes PRC2, leading to H3K27me3 depletion from genes. Targeting G-tract RNA to the tumor suppressor gene CDKN2A in malignant rhabdoid tumor cells reactivates the gene and induces senescence. These data support a model in which pre-mRNA evicts PRC2 during gene activation and provides the means to selectively remove PRC2 from specific genes.


The yeast magmas ortholog pam16 has an essential function in fermentative growth that involves sphingolipid metabolism.
Magmas is a growth factor responsive gene encoding an essential mitochondrial protein in mammalian cells. Pam16, the Magmas ortholog in Saccharomyces cerevisiae, is a component of the presequence translocase-associated motor. A temperature-sensitive allele (pam16-I61N) was used to query an array of non-essential gene-deletion strains for synthetic genetic interactions. The pam16-I61N mutation at ambient temperature caused synthetic lethal or sick phenotypes with genes involved in lipid metabolism, perixosome synthesis, histone deacetylation and mitochondrial protein import. The gene deletion array was also screened for suppressors of the pam16-I61N growth defect to identify compensatory pathways. Five suppressor genes were identified (SUR4, ISC1, IPT1, SKN1, and FEN1) and all are involved in sphingolipid metabolism. pam16-I61N cells cultured in glucose at non-permissive temperatures resulted in rapid growth inhibition and G1 cell cycle arrest, but cell viability was maintained. Altered mitochondria morphology, reduced peroxisome induction in glycerol/ethanol and oleate, and changes in the levels of several sphingolipids including C18 alpha-hydroxy-phytoceramide, were also observed in the temperature sensitive strain. Deletion of SUR4, the strongest suppressor, reversed the temperature sensitive fermentative growth defect, the morphological changes and the elevated levels of C18 alpha-hydroxy phytoceramide in pam16-I61N. Deletion of the other four suppressor genes had similar effects on C18 alpha-hydroxy-phytoceramide levels and restored proliferation to the pam16-I61N strain. In addition, pam16-I61N inhibited respiratory growth, likely by reducing cardiolipin, which is essential for mitochondrial function. Our results suggest that the pleiotropic effects caused by impaired Pam16/Magmas function are mediated in part by changes in lipid metabolism.


Allosteric potentiation of a ligand-gated ion channel is mediated by access to a deep membrane-facing cavity.
Theories of general anesthesia have shifted in focus from bulk lipid effects to specific interactions with membrane proteins. Target receptors include several subtypes of pentameric ligand-gated ion channels; however, structures of physiologically relevant proteins in this family have yet to define anesthetic binding at high resolution. Recent cocrystal structures of the bacterial protein GLIC provide snapshots of state-dependent binding sites for the common surgical agent propofol (PFL), offering a detailed model system for anesthetic modulation. Here, we combine molecular dynamics and oocyte electrophysiology to reveal differential motion and modulation upon modification of a transmembrane binding site within each GLIC subunit. WT channels exhibited net inhibition by PFL, and a contraction of the cavity away from the pore-lining M2 helix in the absence of drug. Conversely, in GLIC variants exhibiting net PFL potentiation, the cavity was persistently expanded and proximal to M2. Mutations designed to favor this deepened site enabled sensitivity even to subclinical concentrations of PFL, and a uniquely prolonged mode of potentiation evident up to ∼30 min after washout. Dependence of these prolonged effects on exposure time implicated the membrane as a reservoir for a lipid-accessible binding site. However, at the highest measured concentrations, potentiation appeared to be masked by an acute inhibitory effect, consistent with the presence of a discrete, water-accessible site of inhibition. These results support a multisite model of transmembrane allosteric modulation, including a possible link between lipid- and receptor-based theories that could inform the development of new anesthetics.


An international overview of resource centers on disability.
Facilities variously known as independent living centers, disabled living centers, disability information centers, and resource centers now exist in many parts of the world. Although occupational therapists offer valuable perspectives on quality of life, knowledge of assistive technology, and a holistic view of clients' needs, occupational therapy is not always a part of these centers. Occupational therapists themselves may overlook these settings as venues for their services. This overview of 38 resource center organizations in 14 countries reports on their approaches to supporting persons with disabilities, professionals, and other members of the public and explores the presence of occupational therapy and other professions in these agencies.


Isotopic, geophysical and biogeochemical investigation of submarine groundwater discharge: IAEA-UNESCO intercomparison exercise at Mauritius Island.
Submarine groundwater discharge (SGD) into a shallow lagoon on the west coast of Mauritius Island (Flic-en-Flac) was investigated using radioactive ((3)H, (222)Rn, (223)Ra, (224)Ra, (226)Ra, (228)Ra) and stable ((2)H, (18)O) isotopes and nutrients. SGD intercomparison exercises were carried out to validate the various approaches used to measure SGD including radium and radon measurements, seepage rate measurements using manual and automated meters, sediment bulk conductivity and salinity surveys. SGD measurements using benthic chambers placed on the floor of the Flic-en-Flac Lagoon showed discharge rates up to 500 cm/day. Large variability in SGD was observed over distances of a few meters, which were attributed to different geomorphological features. Deployments of automated seepage meters captured the spatial and temporal variability of SGD with a mean seepage rate of 10 cm/day. The stable isotopic composition of submarine waters was characterized by significant variability and heavy isotope enrichment and was used to predict the contribution of fresh terrestrially derived groundwater to SGD (range from a few % to almost 100%). The integrated SGD flux, estimated from seepage meters placed parallel to the shoreline, was 35 m(3)/m day, which was in reasonable agreement with results obtained from a hydrologic water balance calculation (26 m(3)/m day). SGD calculated from the radon inventory method using in situ radon measurements were between 5 and 56 m(3)/m per day. Low concentrations of radium isotopes observed in the lagoon water reflected the low abundance of U and Th in the basalt that makes up the island. High SGD rates contribute to high nutrients loading to the lagoon, potentially leading to eutrophication. Each of the applied methods yielded unique information about the character and magnitude of SGD. The results of the intercomparison studies have resulted a better understanding of groundwater-seawater interactions in coastal regions. Such information is an important pre-requisite for the protection and management of coastal freshwater resources.


A Mechanism Study of Electroacupuncture for Dry Eye Syndrome by Targeting Conjunctival Cytokine Expressions.
Aim: To discuss the immunological mechanism in electroacupuncture (EA) treatment of dry eye syndrome (DES) by targeting the changes in conjunctival cytokine expression profile.Method: Eligible DES patients were randomized into an EA group (EAG) or an acupuncture group (AG). The ocular surface disease index (OSDI), amount of tear production, and tear film break-up time (BUT) were observed to evaluate the efficacy. Conjunctival cells were collected from both effective and invalid cases to observe the expressions of cytokines by protein microarray. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for functional cluster and signaling pathway analysis of the differentially expressed proteins. Enzyme-linked immunosorbent assay (ELISA) was used to verify the specific differential proteins.Result: After treatment, OSDI dropped and BUT extended in both groups, and the tear production increased only in the EAG (all P < .01). Compared with the AG, the improvement in tear production was more significant in the EAG (P < .01). There were 17 differentially expressed conjunctival cytokines between the effective and invalid cases in the EAG, and those expressed higher than the limit of detection (LOD) included monocyte chemoattractant protein 1 (MCP-1), macrophage colony-stimulating factor (M-CSF), regulated on activation in normal T-cell expressed and secreted (RANTES) and tissue inhibitor of metalloproteinases 1 (TIMP-1). GO analysis showed that the differential cytokines were mainly involved in cellular interaction, signaling pathways and reactions to stimuli. KEGG analysis revealed that the signaling pathways of these cytokines were mainly responsible for interactions between cytokines or between cytokines and their receptors, such as Jak-STAT signaling pathway, chemokine signaling pathway, and tumor necrosis factor signaling pathway.Conclusion: EA can effectively treat DES by improving the symptoms, increasing tear secretion and extending BUT, which is possibly related to its regulation on the conjunctival cytokine expressions.


Impact of multiple wastewater feedings on the efficiency of nutrient removal in an IFAS-MBSBBR: number of feedings vs. efficiency of nutrient removal.
This article presents the results of research into the influence of one, two and three wastewater feedings in a cycle on efficiency and performance of combined biological nitrogen and phosphorus removal in an integrated fixed-film activated sludge and moving-bed sequencing batch biofilm reactor (IFAS-MBSBBR). The experiment lasted 158 days and was conducted in two laboratory models of the IFAS-MBSBBR with an active volume of 28 L. It was found that along with an increase in the number of wastewater feedings, an increase in nitrogen removal efficiency was observed (from 56.9 ± 2.30% for a single feeding to 91.4 ± 1.77% for three feedings). Moreover, the contribution of simultaneous nitrification/denitrification in nitrogen removal increased (from 2.58% for a single feeding to 69.5% for three feedings). Systems with a greater number of feedings stimulated the process of denitrifying phosphorus removal. Regardless of the way in which wastewater feeding was applied to the IFAS-MBSBBR, highly efficient chemical oxygen demand (COD) removal (94.8 ± 1.80%) and biological phosphorus removal (98.9 ± 0.87%) were achieved.