[Diagnosis of gastroesophageal reflux disease: a systematic review].
The prevalence of gastoesophageal reflux disease (GERD) has been rapidly increased in Korea during last 20 years. However, there has been no systematic review regarding this disease. The aim of this article was to provide a review of available diagnostic modalities for GERD. This review includes proton pump inhibitor (PPI) test, endoscopy, ambulatory pH monitoring, impedance pH monitoring, and esophageal manometry in order to provide a basis for the currently applicable recommendations in the diagnosis of GERD in Korea. With weekly heartburn or acid regurgitation, the prevalence of GERD has been reported as 3.4% to 7.9%, indicating an increase of GERD in Korea. As the prevalence of Barrett's esophagus has been reported to be low, the screening endoscopy for Barrett's esophagus is not recommended. Several recent meta-analyses re-evaluated the value of the PPI test in patients with typical GERD symptoms and non-cardiac chest pain. That is, the PPI test has been proven to be a sensitive tool for diagnosing GERD in patients with non-cardiac chest pain and in some preliminary trials regarding extraesophageal manifestations of GERD. Ambulatory pH monitoring of the esophagus helps to confirm gastroesophageal reflux in patients with persistent symptoms (both typical and atypical) in the absence of esophageal mucosal damage, especially when a trial of acid suppression has failed. Impedance pH test is useful in refractory reflux patients with primary complaints of typical GERD symptoms, but this value has not been proved in patients with non-cardiac chest pain or extraesophageal symptoms. This systematic review is targeted to establish the strategy of GERD diagnosis, which is essential for the current clinical practice.


Chlorine-Coordinated Unsaturated Ni-N2 Sites for Efficient Electrochemical Carbon Dioxide Reduction.
Heteroatom-doping is an effective method for modifying the geometric symmetry of metal-nitrogen-carbon (M-N-C) single-atom catalysts and thereby tuning the electronic structure. Up to now, most of the current reports have concentrated on introducing heteroatoms into the highly symmetrical M-N4 structure. The coordination-unsaturated M-N2 structure is more sterically favorable for the insertion of alien atoms to optimize the electronic structure. Herein, a Ni-N2 catalyst with out-of-plane coordinated chlorine (Cl) atoms (Ni-N2 Cl/C) is successfully constructed on chlorine-functionalized carbon supports (C-Cl) for an efficient carbon dioxide reduction reaction (CO2 RR). Density functional theory calculations demonstrate that the prepared Ni-N2 Cl/C catalyst exhibits a higher capability in balancing COOH* formation and CO* desorption. In addition, in situ Raman spectra confirm that the lower CO binding energy on the Ni-N2 Cl/C facilitates CO escape, leading to excellent CO2 RR performance. A high CO Faradaic efficiency (FECO ) of more than 80% is achieved from -0.6 to -1.2 V versus reversible hydrogen electrode on the Ni-N2 Cl/C and it exhibits negligible FECO and current declination over a 40-h stability test. Furthermore, a high turnover frequency (TOF) value of 15 808 h-1 is obtained, which is more than ten times that of Ni-N2 /C (1476 h-1 ) without coordinated Cl atoms.


Human herpesvirus-8 infection of primary pulmonary microvascular endothelial cells.
Human herpesvirus-8 (HHV-8) is the causative agent of Kaposi's sarcoma and is associated with the angioproliferative disorders primary effusion lymphoma and multicentric Castleman's disease. Evidence of HHV-8 infection within the pulmonary vasculature of patients with idiopathic pulmonary arterial hypertension (IPAH) has been described. We hypothesize that HHV-8 infection of pulmonary microvascular endothelial cells results in an apoptotic-resistant phenotype characteristic of severe pulmonary arterial hypertension. Our objective was to investigate the ability of HHV-8 to infect human pulmonary microvascular endothelial cells in vitro and characterize the phenotypic effect of this infection. Human pulmonary microvascular endothelial cells were exposed to HHV-8 using two methods (direct virus and co-culture technique). The presence of lytic and latent infection was confirmed. Changes in endothelial cell gene and protein expression and effects on cellular apoptosis were measured. HHV-8 can both lytically and latently infect primary human pulmonary microvascular endothelial cells in vitro. HHV-8 infection results in significant changes in gene expression, including alterations of pathways important to cellular apoptosis. HHV-8 infection also alters expression of genes integral to the bone morphogenic protein pathway, including down-regulation of bone morphogenic protein-4. Other genes previously implicated in the development of PAH are affected by HHV-8 infection, and cells infected with HHV-8 are resistant to apoptosis.


Use of brachial plexus blockade and medetomidine-ketamine-isoflurane anaesthesia for repair of radio-ulna fracture in an adult cheetah (Acinonyx jubatus).
Regional anaesthetic techniques have been used in combination with systemic analgesics during small animal surgery to provide multimodal analgesia. Brachial plexus nerves block using local anaesthetics provides analgesia of the thoracic limb through desensitization of the nerves that provide sensory and motor innervation. This has been shown to reduce intra-operative anesthetic requirements and provide postoperative pain relief. Decreasing the doses of general anaesthetics allows more stable cardiopulmonary function during anaesthesia and the development of less side effects. The present case reports a successful use of brachial plexus blockade to supplement medetomidine-ketamine-isoflurane anaesthesia for repair of radio-ulna fracture in an adult cheetah (acinonyx jubatus). An adult male Cheetah weighing about 65 kg was presented with a history of leg carrying lameness of the left forelimb sustained following a car accident a week earlier. Clinical examination under general anaesthesia revealed slight dehydration and a swelling with a wound on the caudo-medial aspect of the left radio-ulna region. Crepitation was present on manipulation and radiography confirmed a complete transverse radio-ulna fracture of the left forelimb, which required open reduction and internal fixation. Brachial plexus blockade using lignocaine hydrochloride was used to supplement medetomidine-ketamine-isoflurane anaesthesia for the surgical procedure. Isoflurane anaesthesia was maintained at 0.5 - 2.0% throughout the surgical procedure, which was uneventful. Temperature and cardio-pulmonary parameters remained stable intra-operatively. Limb paralysis extended for 5 hours post-operatively, suggesting prolonged anaesthesia. To the researchers' knowledge, this is the first reported case of the use of brachial plexus blockade to supplement general anaesthesia to facilitate forelimb surgery in an adult cheetah. The use of brachial plexus block with a light plane of general anaesthesia proved to be successful. Brachial plexus block had a sparing effect on isoflurane anaesthesia as evidenced by the concentration used for maintenance of anaesthesia and the stability of the cardiopulmonary function. Moreover, absence of autonomic cardiopulmonary reactions to the surgical manipulation may be attributed to the efficacy of brachial plexus block. This anaesthesia protocol is therefore recommended for surgeries of the forelimb in wild cats.


[CO2 flux characteristics and their influence on the carbon budget of a larch plantation in Maoershan region of Northeast China].
From January to December 2008, the CO2 flux in a larch plantation (Larix gmeilinii) in Maoershan region of Shangzhi County, Heilongliang Province was measured by eddy covanance method, and the diurnal changes of leaf photosynthetic rate were measured in growth season (from May to October). There existed differences in the net ecosystem exchange (NEE) of the plantation in different time periods under the effects of environmental factors. In the afternoon (12:00-24:00), the NEE changed more slowly with the variation of vapor pressure deficit (VPD) than in the morning (0:00-12:00); and in the morning, tbe light use efficiency was 0.6284 mol x mol(-1), 14% more than that in afternoon. The NEE increased with increasing temperature, and the increment in the morning was 50% higher than that in the afternoon (air temperature > 15 degrees C). These differences in responding to environmental changes led to 88% NEE implemented in the morning, and only 12% NEE implemented in the afternoon. The annual gross ecosystem productivity (GEP) in the morning took a percentage of 60%, and that in afternoon took 40%. These findings were supported by the observation at leaf level, i.e., on average of whole growth season, the leaf photosynthetic capacity in the morning was over 2-fold higher than that in afternoon. Generally, the annual NEE, ecosystem respiration (Re), and GEP of the plantation in 2008 were 263-264 g C x m(-2), 718-725 g C x m(-2), and 981-989 g C x m(-2), respectively.


Retinal Thickness Analysis in Progressive Multiple Sclerosis Patients Treated With Epigallocatechin Gallate: Optical Coherence Tomography Results From the SUPREMES Study.
Background: Epigallocatechin gallate (EGCG) is an anti-inflammatory agent and has proven neuroprotective properties in animal models of multiple sclerosis (MS). Optical coherence tomography (OCT) assessed retinal thickness analysis can reflect treatment responses in MS. Objective: To analyze the influence of EGCG treatment on retinal thickness analysis as secondary and exploratory outcomes of the randomized controlled Sunphenon in Progressive Forms of MS trial (SUPREMES, NCT00799890). Methods: SUPREMES patients underwent OCT with the Heidelberg Spectralis device at a subset of visits. We determined peripapillary retinal nerve fiber layer (pRNFL) thickness from a 12° ring scan around the optic nerve head and thickness of the ganglion cell/inner plexiform layer (GCIP) and inner nuclear layer (INL) within a 6 mm diameter grid centered on the fovea from a macular volume scan. Longitudinal OCT data were available for exploratory analysis from 31 SUPREMES participants (12/19 primary/secondary progressive MS (PPMS/SPMS); mean age 51 ± 7 years; 12 female; mean time since disease onset 16 ± 11 years). We tested the null hypothesis of no treatment*time interaction using nonparametric analysis of longitudinal data in factorial experiments. Results: After 2 years, there were no significant differences in longitudinal retinal thickness changes between EGCG treated and placebo arms in any OCT parameter (Mean change [confidence interval] ECGC vs. Placebo: pRNFL: -0.83 [1.29] μm vs. -0.64 [1.56] μm, p = 0.156; GCIP: -0.67 [0.67] μm vs. -0.14 [0.47] μm, p = 0.476; INL: -0.06 [0.58] μm vs. 0.22 [0.41] μm, p = 0.455). Conclusion: Retinal thickness analysis did not reveal a neuroprotective effect of EGCG. While this is in line with the results of the main SUPREMES trial, our study was probably underpowered to detect an effect. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT00799890.


Ethnic differences in tissue creatine kinase activity: an observational study.
Serum creatine kinase (CK) levels are reported to be around 70% higher in healthy black people, as compared to white people (median value 88 IU/L in white vs 149 IU/L in black people). As serum CK in healthy people is thought to occur from a proportional leak from normal tissues, we hypothesized that the black population subgroup has a generalized higher CK activity in tissues. We compared CK activity spectrophotometrically in tissues with high and fluctuating energy demands including cerebrum, cerebellum, heart, renal artery, and skeletal muscle, obtained post-mortem in black and white men. Based on serum values, we conservatively estimated to find a 50% greater CK activity in black people compared with white people, and calculated a need for 10 subjects of one gender in each group to detect this difference. We used mixed linear regression models to assess the possible influence of ethnicity on CK activity in different tissues, with ethnicity as a fixed categorical subject factor, and CK of different tissues clustered within one person as the repeated effect response variable. We collected post-mortem tissue samples from 17 white and 10 black males, mean age 62 y (SE 4). Mean tissue CK activity was 76% higher in tissues from black people (estimated marginal means 107.2 [95% CI, 76.7 to 137.7] mU/mg protein in white, versus 188.6 [148.8 to 228.4] in black people, p = 0.002). We found evidence that black people have higher CK activity in all tissues with high and fluctuating energy demands studied. This finding may help explain the higher serum CK levels found in this population subgroup. Furthermore, our data imply that there are differences in CK-dependent ATP buffer capacity in tissue between the black and the white population subgroup, which may become apparent with high energy demands.


Discovery and analysis of consistent active sub-networks in cancers.
Gene expression profiles can show significant changes when genetically diseased cells are compared with non-diseased cells. Biological networks are often used to identify active subnetworks (ASNs) of the diseases from the expression profiles to understand the reason behind the observed changes. Current methodologies for discovering ASNs mostly use undirected PPI networks and node centric approaches. This can limit their ability to find the meaningful ASNs when using integrated networks having comprehensive information than the traditional protein-protein interaction networks. Using appropriate scoring functions to assess both genes and their interactions may allow the discovery of better ASNs. In this paper, we present CASNet, which aims to identify better ASNs using (i) integrated interaction networks (mixed graphs), (ii) directions of regulations of genes, and (iii) combined node and edge scores. We simplify and extend previous methodologies to incorporate edge evaluations and lessen their sensitivity to significance thresholds. We formulate our objective functions using mixed integer programming (MIP) and show that optimal solutions may be obtained. We compare the ASNs obtained by CASNet and similar other approaches to show that CASNet can often discover more meaningful and stable regulatory ASNs. Our analysis of a breast cancer dataset finds that the positive feedback loops across 7 genes, AR, ESR1, MYC, E2F2, PGR, BCL2 and CCND1 are conserved across the basal/triple negative subtypes in multiple datasets that could potentially explain the aggressive nature of this cancer subtype. Furthermore, comparison of the basal subtype of breast cancer and the mesenchymal subtype of glioblastoma ASNs shows that an ASN in the vicinity of IL6 is conserved across the two subtypes. This result suggests that subtypes of different cancers can show molecular similarities indicating that the therapeutic approaches in different types of cancers may be shared.


Cerebral function monitoring in paediatric intensive care: useful features for predicting outcome.
Neurological integrity in sick children is difficult to assess clinically. The aim of this study was to determine the predictive value of EEG activity recorded with a bedside EEG analysing monitor in an intensive care unit. EEG activity was monitored in 108 children (age range 2 weeks to 16 years, median 1.7 years) considered at risk for cerebral abnormalities with a cerebral function analysing monitor (CFAM). Recordings were evaluated for features of background EEG activity including mean amplitude, frequencies, and symmetry. Electrical seizure activity was quantified if present. Predictive value of the EEG features was evaluated relative to the clinical neurological outcome after one year. Asymmetrical recordings were not seen in any child with a normal outcome. Suppression of background activity was seen in 75% of the children who died. Seizures were present in 68% of children with a poor outcome. Seventeen of the 32 children (65%) who died had prolonged seizures. Absence of seizures and the presence of superimposed fast EEG activity in response to benzodiazepine infusions correlated with good outcome. A combination of two or more predictive EEG features demonstrated >90% specificity and positive predictive likelihood of poor outcome. EEG features provide information about the functional cerebral integrity of sick children. Changes in cerebral activity detected by the CFAM aid decision making by providing such information readily at the bedside in intensive care.


WebPPG: Feasibility and Usability of Self-Performed, Browser-Based Smartphone Photoplethysmography.
Smartphones enable and facilitate biomedical studies as they allow the recording of various biomedical signals, including photoplethysmograms (PPG). However, user engagement rates in mobile health studies are reduced when an application (app) needs to be installed. This could be alleviated by using installation-free web apps. We evaluate the feasibility of browser-based PPG recording, conducting the first usability study on smartphone-based PPG. We present an at-home study using a web app and library for PPG recording using the rear camera and flash. The underlying library is freely made available to researchers. 25 Android users participated, using their own smartphones. The study consisted of a demographic and anamnestic questionnaire, the signal recording itself (60 s), and a consecutive usability questionnaire. After filtering, heart rate was extracted (14/17 successful), signal-to-noise ratios assessed (0.64 ± 0.50 dB, mean ± standard deviation), and quality was visually inspected (12/17 usable for diagnosis). Recording was not supported in 9 cases. This was due to the browser's insufficient support for the flash light API. The app received a System Usability Scale score of 82 ± 9, which is above the 90th percentile. Overall, browser flash light support is the main limiting factor for broad device support. Thus, browser-based PPG is not yet widely applicable, although most participants feel comfortable with the recording itself. The utilization of the user-facing camera might represent a more promising approach. This study contributes to the development of low-barrier, user-friendly, installation-free smartphone signal acquisition. This enables profound, comprehensive data collection for research and clinical practice.Clinical relevance- WebPPG offers low-barrier remote diagnostic capabilities without the need for app installation.


Nucleic Acid-Based Approaches to Tackle KRAS Mutant Cancers.
Activating mutations in KRAS are highly relevant to various cancers, driving persistent efforts toward the development of drugs that can effectively inhibit KRAS activity. Previously, KRAS was considered 'undruggable'; however, the recent advances in our understanding of RNA and nucleic acid chemistry and delivery formulations have sparked a paradigm shift in the approach to KRAS inhibition. We are currently witnessing a large wave of next-generation drugs for KRAS mutant cancers-nucleic acid-based therapeutics. In this review, we discuss the current progress in targeting KRAS mutant tumors and outline significant developments in nucleic acid-based strategies. We delve into their mechanisms of action, address existing challenges, and offer insights into the current clinical trial status of these approaches. We aim to provide a thorough understanding of the potential of nucleic acid-based strategies in the field of KRAS mutant cancer therapeutics.


Direct type I IFN but not MDA5/TLR3 activation of dendritic cells is required for maturation and metabolic shift to glycolysis after poly IC stimulation.
Type I interferons (IFNs) play an important role in direct antiviral defense as well as linking the innate and adaptive immune responses. On dendritic cells (DCs), IFNs facilitate their activation and contribute to CD8(+) and CD4(+) T cell priming. However, the precise molecular mechanism by which IFNs regulate maturation and immunogenicity of DCs in vivo has not been studied in depth. Here we show that, after in vivo stimulation with the TLR ligand poly IC, IFNs dominate transcriptional changes in DCs. In contrast to direct TLR3/mda5 signaling, IFNs are required for upregulation of all pathways associated with DC immunogenicity. In addition, metabolic pathways, particularly the switch from oxidative phosphorylation to glycolysis, are also regulated by IFNs and required for DC maturation. These data provide evidence for a metabolic reprogramming concomitant with DC maturation and offer a novel mechanism by which IFNs modulate DC maturation.


Functional gastrointestinal disorders in unselected patients with non-cardiac chest pain.
Patients with non-cardiac chest pain (NCCP) (n = 387) and cardiac chest pain (CCP) (n = 93) were compared with community controls (n = 81), using a symptom questionnaire that assessed the presence of irritable bowel syndrome (IBS), functional dyspepsia, and oesophageal dysfunction and chest pain characteristics. A significantly (p < 0.05) increased prevalence of symptoms compatible with IBS occurred in NCCP patients when compared with those with CCP and with controls. Dysphagia was more frequent in both those with non-cardiac and cardiac chest pain than in controls; this was not apparent, however, when patients with concomitant IBS were excluded. The presence of oesophageal or gastrointestinal symptoms did not enable discrimination with regard to the chest pain characteristics. We conclude that unselected referred patients with documented NCCP are more likely to have IBS and that the presence of oesophageal symptoms such as dysphagia may merely reflect the spectrum of the 'irritable gut'.


Studies on the incorporation of membrane proteins into liposomes: --effect of "boundary lipids" on reconstitution of pig heart mitochondrial cytochrome oxidase into liposomes.
The reactivation of delipidated cytochrome oxidase depends on the reformation of "annular lipids", which is tightly bounded to the enzyme molecule. In the restoration of oxidase activity, the efficiencies of phospholipids with different polar head groups decrease in this order: PS greater than DPG greater than PI greater than PA greater than PG greater than PC, PE and in the case of phosphatidylcholines with different acyl chain the order is DOPC greater than LPC greater than PC greater than DPPC, DSPC. Therefore both the polar head group and the acyl chain of phospholipids must be considered in the reactivation process. The existence and the specificity of "annular lipids" obviously influence the incorporation of cytochrome oxidase into liposomes. When acidic phospholipids are used as "annular lipids", the effectiveness of reconstitution decreases in this order: PI greater than PS greater than DPG greater than PA, PG. Divalent metallic cations would facilitate the cytochrome oxidase reconstitution, but their effects depend on the composition of "annular lipids". Using dialysis method Ca2+ and Mg2+ could facilitate the incorporation into liposomes of the enzymes having PS or DOPC as their "boundary lipids". A comparison between the effects of different metallic cations on incorporation of cytochrome oxidase also shows that, with PI as "annular lipids", the effectiveness of different cations on incorporation by incubation method decreases in this order: Ca2+ greater than Mg2+ greater than Mn2+, Sr2+ greater than La3+. Apparently, the effect of metallic cations on incorporation cannot be interpreted by considering only the neutralization of the negative charged groups on membrane protein and lipids.


Maximally effective dosing regimens of meropenem in patients with septic shock.
To use a population pharmacokinetic approach to define maximally effective meropenem dosing recommendations for treatment of Acinetobacter baumannii and Pseudomonas aeruginosa infections in a large cohort of patients with septic shock. Adult patients with septic shock and conserved renal function, treated with meropenem, were eligible for inclusion. Seven blood samples were collected during a single dosing interval and meropenem concentrations were measured by a validated HPLC-MS/MS method. Monte Carlo simulations were employed to define optimum dosing regimens for treatment of empirical or targeted therapy of A. baumannii and P. aeruginosa. EudraCT-no. 2014-002555-26 and NCT02240277. Fifty patients were included, 26 male and 24 female, with a median age of 64 years with an all-cause 90 day mortality of 34%. A two-compartment linear model including creatinine clearance (CLCR) as a covariate best described meropenem pharmacokinetics. For empirical treatment of A. baumannii, 2000 mg/6 h was required by intermittent (30 min) or prolonged (3 h) infusion, whereas 6000 mg/day was required with continuous infusion. For P. aeruginosa, 2000 mg/8 h or 1000 mg/6 h was required for both empirical and targeted treatment. In patients with a CLCR of ≤ 100 mL/min, successful concentration targets could be reached with intermittent dosing of 1000 mg/8 h. In patients with septic shock and possible augmented renal clearance, doses should be increased and/or administration should be performed by prolonged or continuous infusion to increase the likelihood of achieving therapeutic drug concentrations. In patients with normal renal function, however, standard dosing seems to be sufficient.


Self-Supervised Learning of Graph Neural Networks: A Unified Review.
Deep models trained in supervised mode have achieved remarkable success on a variety of tasks. When labeled samples are limited, self-supervised learning (SSL) is emerging as a new paradigm for making use of large amounts of unlabeled samples. SSL has achieved promising performance on natural language and image learning tasks. Recently, there is a trend to extend such success to graph data using graph neural networks (GNNs). In this survey, we provide a unified review of different ways of training GNNs using SSL. Specifically, we categorize SSL methods into contrastive and predictive models. In either category, we provide a unified framework for methods as well as how these methods differ in each component under the framework. Our unified treatment of SSL methods for GNNs sheds light on the similarities and differences of various methods, setting the stage for developing new methods and algorithms. We also summarize different SSL settings and the corresponding datasets used in each setting. To facilitate methodological development and empirical comparison, we develop a standardized testbed for SSL in GNNs, including implementations of common baseline methods, datasets, and evaluation metrics.


Using changes in speciation in a dynamic combinatorial library as a fingerprint to differentiate the methylation states of arginine.
Herein we describe the development of a sensor array that utilizes the complex response of a dynamic combinatorial library (DCL) to discriminate all of the methylation states of Arg, previously unreported in a sensor array, as well as the methylation states of Lys. We find that the use of all species in the DCL, not just those that bind, allows for discrimination of analytes that are otherwise indistinguishable, demonstrating the value of utilizing a complex network of species for differential sensing.


Comparative release kinetics of small drugs (ibuprofen and acetaminophen) from multifunctional mesoporous silica nanoparticles.
Multifunctional mesoporous silica nanoparticles (MSNs) can confer dynamically varied release kinetics depending on the intermolecular interactions between model drugs and functional decorations on the MSNs. Herein, brush-like fluorescent conjugates were grafted on the pore walls of pristine MSNs for high drug loading and to impart fluorescence properties. The fluorescent MSNs (FMSNs) were further coated with polydopamine (PDA) and graphene oxide (GO) double layer, designated FMSNs@PDA and FMSNs@PDA@GO, respectively. The FMSNs@PDA@GO exhibited highly consistent drug release over one week (∼7 days) because of the consolidated PDA/GO double layer at neutral pH (7.4). However, the release rate of FMSN-Ibu@PDA@GO was increased at acidic pH (5.5) because the PDA/GO double layer was partially disrupted due to weakened π-π stacking and electrostatic interactions. The release kinetics of the FMSNs-based NPs (FMSNs, FMSNs@PDA, and FMSNs@PDA@GO) were systematically investigated using negatively charged hydrophobic ibuprofen and neutral hydrophilic acetaminophen at pH 7.4. In the FMSN-drug system, the release rate of acetaminophen was higher than that of ibuprofen because of the higher solubility of acetaminophen in aqueous solution. In addition, ibuprofen has a bulky molecular structure compared to acetaminophen, leading to its slower transmission through the porous channels of FMSNs. In the FMSNs-drug@PDA system, acetaminophen exhibited a slower release rate than ibuprofen, owing to the π-π stacking interactions in the transmission of neutral acetaminophen by the PDA coating layer. On the other hand, the FMSNs-drug@PDA@GO exhibited a slower ibuprofen release rate than acetaminophen, owing to the electrostatic repulsion effect of the negative GO layer. Our drug delivery system was demonstrated as an advanced delivery platform, in which the transmission rate is controlled by intermolecular interactions between the diffusing drugs and functional decorations on the nanocarrier.


Effects of Repeated Lipopolysaccharide Treatment on Growth Performance, Immune Organ Index, and Blood Parameters of Sprague-Dawley Rats.
The study was designed to investigate the effects of repeated lipopolysaccharide (LPS) treatment on growth performance, lymphoid organ indexes, and blood cells in Sprague-Dawley rats. Forty healthy weaned Sprague-Dawley rats were randomly equally divided into LPS and control groups. Each rat in the LPS group was injected via the caudal vein with LPS (100 μg/kg b.w.) for 10 days, and the control group was treated with an equal volume of normal saline. On the 1st, 4th, 7th, and 10th days, growth performance, lymphoid organ indexes, and blood cells were evaluated in five necropsied rats. When rats were treated 3-10 times with LPS, their body weight and average daily gains increased more slowly than in the control group (P < 0.05). Repeated LPS treatment significantly increased spleen weight and the ratio of spleen to body weight (P < 0.05). White blood cells, neutrophils, and neutrophil percentage increased (P < 0.05) remarkably, but lymphocyte percentage, haemoglobin, and blood platelet counts decreased significantly (P < 0.05). LPS treatment obviously suppresses growth and promotes peripheral immune organ proliferation. It is indicated that host protective mechanism can be activated by multiple small doses of LPS and prevents organs from further damage during stress status.


TLR5 signaling stimulates the innate production of IL-17 and IL-22 by CD3(neg)CD127+ immune cells in spleen and mucosa.
In adaptive immunity, Th17 lymphocytes produce the IL-17 and IL-22 cytokines that stimulate mucosal antimicrobial defenses and tissue repair. In this study, we observed that the TLR5 agonist flagellin induced swift and transient transcription of genes encoding IL-17 and IL-22 in lymphoid, gut, and lung tissues. This innate response also temporarily enhanced the expression of genes associated with the antimicrobial Th17 signature. The source of the Th17-related cytokines was identified as novel populations of CD3(neg)CD127(+) immune cells among which CD4-expressing cells resembling lymphoid tissue inducer cells. We also demonstrated that dendritic cells are essential for expression of Th17-related cytokines and so for stimulation of innate cells. These data define that TLR-induced activation of CD3(neg)CD127(+) cells and production of Th17-related cytokines may be crucial for the early defenses against pathogen invasion of host tissues.


Characterization of glyphosate-resistant Burkholderia anthina and Burkholderia cenocepacia isolates from a commercial Roundup® solution.
Roundup® is the brand name for herbicide solutions containing glyphosate, which specifically inhibits the 5-enolpyruvyl-shikimate-3-phosphate (EPSP) synthase of the shikimate pathway. The inhibition of the EPSP synthase causes plant death because EPSP is required for biosynthesis of aromatic amino acids. Glyphosate also inhibits the growth of archaea, bacteria, Apicomplexa, algae and fungi possessing an EPSP synthase. Here, we have characterized two glyphosate-resistant bacteria from a Roundup solution. Taxonomic classification revealed that the isolates 1CH1 and 2CH1 are Burkholderia anthina and Burkholderia cenocepacia strains respectively. Both isolates cannot utilize glyphosate as a source of phosphorus and synthesize glyphosate-sensitive EPSP synthase variants. Burkholderia. anthina 1CH1 and B. cenocepacia 2CH1 tolerate high levels of glyphosate because the herbicide is not taken up by the bacteria. Previously, it has been observed that the exposure of soil bacteria to herbicides like glyphosate promotes the development of antibiotic resistances. Antibiotic sensitivity testing revealed that the only the B. cenocepacia 2CH1 isolate showed increased resistance to a variety of antibiotics. Thus, the adaptation of B. anthina 1CH1 and B. cenocepacia 2CH1 to glyphosate did not generally increase the antibiotic resistance of both bacteria. However, our study confirms the genomic adaptability of bacteria belonging to the genus Burkholderia.


The thalidomide analgesic effect is associated with differential TNF-α receptor expression in the dorsal horn of the spinal cord as studied in a rat model of neuropathic pain.
The proinflammatory cytokine tumor necrosis factor-α (TNF-α) is well recognized as a key player in nociceptive signaling. Yet, therapeutic capitalization of this knowledge requires a better understanding of how TNF receptors (TNFR) contribute to pain. To address this question, we studied TNFR expression in the chronic sciatic nerve constriction (CCI) model of neuropathic pain. CCI and sham operated rats received two subcutaneous injections (one immediately after surgery, the other on postoperative day 5) containing either saline, GABA-reuptake inhibitor (NO-711), insulin-like growth factor-1 (IGF-1), ZVAD or thalidomide. Mechanical (using von Frey filaments) and thermal hypersensitivity (Hargreaves test) were assessed preoperatively and weekly during the first four postoperative weeks. Spinal cord dorsal horn samples were collected from animals that were sacrificed at 2 weeks and 4 weeks after surgery, and analyzed for TNFR1 and TNFR2 mRNA levels by qPCR and protein levels by Western blot. Compared to saline, all applied drug treatments resulted in a faster recovery from mechanical and thermal hypersensitivity, yet in a potency order of thalidomide>ZVAD=IGF-1>NO-711. CCI resulted in increased TNFR1 and TNFR2 mRNA and protein levels in the ipsilateral dorsal horn. Thalidomide was the only treatment that attenuated these increases. Finally, animals that showed a poor behavioral recovery were characterized by a significantly higher TNFR1/TNFR2 mRNA ratio. These data show that differential expression of TNFR in the dorsal horn is associated with recovery from pain in this model and suggest that the analgesic effects of thalidomide may act via this mechanism.


Cerebellar and basal ganglia inputs define three main nuclei in the mouse ventral motor thalamus.
The thalamus is a central link between cortical and subcortical brain motor systems. Axons from the deep nuclei of the cerebellum (DCN), or the output nuclei of the basal ganglia system (substantia nigra reticulata, SNr; and internal pallidum GPi/ENT) monosynaptically innervate the thalamus, prominently some nuclei of the ventral nuclear group. In turn, axons from these ventral nuclei innervate the motor and premotor areas of the cortex, where their input is critical for planning, execution and learning of rapid and precise movements. Mice have in recent years become a widely used model in motor system research. However, information on the distribution of cerebellar and basal ganglia inputs in the rodent thalamus remains poorly defined. Here, we mapped the distribution of inputs from DCN, SNr, and GPi/ENT to the ventral nuclei of the mouse thalamus. Immunolabeling for glutamatergic and GABAergic neurotransmission markers delineated two distinct main territories, characterized each by the presence of large vesicular glutamate transporter type 2 (vGLUT2) puncta or vesicular GABA transporter (vGAT) puncta. Anterograde labeling of axons from DCN revealed that they reach virtually all parts of the ventral nuclei, albeit its axonal varicosities (putative boutons) in the vGAT-rich sector are consistently smaller than those in the vGLUT2-rich sector. In contrast, the SNr axons innervate the whole vGAT-rich sector, but not the vGLUT2-rich sector. The GPi/ENT axons were found to innervate only a small zone of the vGAT-rich sector which is also targeted by the other two input systems. Because inputs fundamentally define thalamic cell functioning, we propose a new delineation of the mouse ventral motor nuclei that is consistent with the distribution of DCN, SNr and GPi/ENT inputs and resembles the general layout of the ventral motor nuclei in primates.


Efficacy and safety of oral mirodenafil in the treatment of erectile dysfunction in diabetic men in Korea: a multicenter, randomized, double-blind, placebo-controlled clinical trial.
Mirodenafil is a newly developed selective phosphodiesterase type 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED). To evaluate the efficacy, safety and tolerability of mirodenafil in the treatment of ED in Korean men with diabetes. A multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study was conducted with 112 subjects who were randomized to either placebo or mirodenafil 100 mg on demand for 12 weeks. Primary efficacy variable was the erectile function (EF) domain scores of the International Index of Erectile Dysfunction (IIEF) questionnaire. Secondary efficacy variables included change in the scores of IIEF question 3 and 4 (IIEF Q3 and Q4) from baseline, change in all domain scores in the IIEF from baseline, Sexual Encounter Profile questions 2 and 3 (SEP2 and SEP3), the Global Assessment Question (GAQ) and the Life Satisfaction Checklist (LSC). After 12 weeks of treatment, mirodenafil group showed significantly greater change in the IIEF-EF domain score from baseline compared with the placebo group (9.3 vs. 1.4, P < 0.0001). The changes from baseline in the mirodenafil group in IIEF Q3 (1.7 vs. 0.4, P < 0.0001) and Q4 (1.7 vs. 0.3, P < 0.0001) were higher compared with the placebo group. Differences between the mirodenafil and placebo groups were significant in the SEP2 (82.0% vs. 55.2%, P = 0.0003), SEP3 (68.9% vs. 22.3%, P < 0.0001). Difference in GAQ "YES" responses was also significant (76.9% vs. 19.1%, P < 0.0001). Normal EF domain scores (≥ 26) at study end were achieved by 32.7% and 9.4% in the mirodeniafl and placebo groups, respectively (P = 0.0031). As for the LSC scores, the mirodenafil group showed significantly greater improvements in sexual life and partner relationship than the placebo group. Most treatment-associated AEs were mild that resolved spontaneously. Mirodenafil is an effective and well-tolerated agent for the treatment of diabetic patients with ED in Korea.


Ultrafine Entanglement Witnessing.
Entanglement witnesses are invaluable for efficient quantum entanglement certification without the need for expensive quantum state tomography. Yet, standard entanglement witnessing requires multiple measurements and its bounds can be elusive as a result of experimental imperfections. Here, we introduce and demonstrate a novel procedure for entanglement detection which simply and seamlessly improves any standard witnessing procedure by using additional available information to tighten the witnessing bounds. Moreover, by relaxing the requirements on the witness operators, our method removes the general need for the difficult task of witness decomposition into local observables. We experimentally demonstrate entanglement detection with our approach using a separable test operator and a simple fixed measurement device for each agent. Finally, we show that the method can be generalized to higher-dimensional and multipartite cases with a complexity that scales linearly with the number of parties.


[Treatment strategy for activating EGFR-mutated non-small cell lung cancer after failure of first-generation EGFR-TKIs].
Somatic activating mutations such as a deletion in exon 19 or the missense mutation L858R in the tyrosine kinase domain of the epidermal growth factor receptor(EGFR)are important mediators of cancer cell oncogenesis, proliferation, and survival. In the last decade, two EGFR target agents have significantly contributed to the understanding of non-small cell lung cancer (NSCLC). Gefitinib and erlotinib are first-generation EGFR-tyrosine kinase inhibitors(EGFR-TKIs)that play a key role in activating EGFR-mutated NSCLC. Although these reversible, small, molecular target agents provide a significant response and survival benefit, all responders eventually acquire resistance. Although various mechanisms of resistance have been identified, nearly 3 0% of patients who acquire resistance to EGFR-TKIs have an unknown mechanism of resistance. Approximately half the patients with EGFR-mutated NSCLC who develop acquired resistance to these molecular target agents have a secondary mutation T790M in the threonine gatekeeper residue that coexists with a primary EGFR activating mutation. The strategy for overcoming acquired resistance to first-generation EGFR-TKIs is a major clinical concept. Afatinib is a second-generation EGFR-targeting agent and an irreversible pan-HER inhibitor. It may improve survival further and help in potentially overcoming resistance to first-generation EGFR-TKIs in EGFR-mutated NSCLC. In patients harboring activating EGFR mutations, certain treatments could be suggested for subsequent therapy after failure of first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for activating EGFR-mutated, advanced NSCLC after failure of first-generation EGFR-TKIs.


Contributions of DNA Damage to Alzheimer's Disease.
Alzheimer's disease (AD) is the most common type of neurodegenerative disease. Its typical pathology consists of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Mutations in the APP, PSEN1, and PSEN2 genes increase Aβ production and aggregation, and thus cause early onset or familial AD. Even with this strong genetic evidence, recent studies support AD to result from complex etiological alterations. Among them, aging is the strongest risk factor for the vast majority of AD cases: Sporadic late onset AD (LOAD). Accumulation of DNA damage is a well-established aging factor. In this regard, a large amount of evidence reveals DNA damage as a critical pathological cause of AD. Clinically, DNA damage is accumulated in brains of AD patients. Genetically, defects in DNA damage repair resulted from mutations in the BRAC1 and other DNA damage repair genes occur in AD brain and facilitate the pathogenesis. Abnormalities in DNA damage repair can be used as diagnostic biomarkers for AD. In this review, we discuss the association, the causative potential, and the biomarker values of DNA damage in AD pathogenesis.


[Geriatric approach of sleep disorders in the elderly].
Sleep complaints and disorders are frequent in geriatric patients, with a prevalence of 57%. They result in increased morbidity and mortality. In this population, the primary goal is to search for a cause of secondary insomnia, such as organic or psychiatric diseases, or medications. In those cases, sleep will improve with the treatment of the cause. In the cases of primary insomnia, behavioral and sleep hygiene therapy are essential. Hypnotics have frequent side effects and should be avoided when possible. Prescription of small doses of benzodiazepines or related drugs should only be for a short period of time. Molecules with a short half life are to be preferred. Other sleep disorders include sleep apnea syndrome, restless legs syndrome and periodic limb movements, which are the most frequent diagnoses in an elderly population. In the restless legs syndrome, diagnostic workup must include the search for a cause and treatment should favor hygienic measures. The use of dopamine agonists must be cautious, as their tolerance is poor in the elderly. Periodic limb movements are also frequent but there is no particular therapeutic recommendation.


BAYESIAN SHRINKAGE METHODS FOR PARTIALLY OBSERVED DATA WITH MANY PREDICTORS.
Motivated by the increasing use of and rapid changes in array technologies, we consider the prediction problem of fitting a linear regression relating a continuous outcome Y to a large number of covariates X , eg measurements from current, state-of-the-art technology. For most of the samples, only the outcome Y and surrogate covariates, W , are available. These surrogates may be data from prior studies using older technologies. Owing to the dimension of the problem and the large fraction of missing information, a critical issue is appropriate shrinkage of model parameters for an optimal bias-variance tradeoff. We discuss a variety of fully Bayesian and Empirical Bayes algorithms which account for uncertainty in the missing data and adaptively shrink parameter estimates for superior prediction. These methods are evaluated via a comprehensive simulation study. In addition, we apply our methods to a lung cancer dataset, predicting survival time (Y) using qRT-PCR ( X ) and microarray ( W ) measurements.


Emergence of periodic order in electric-field-driven planar nematic liquid crystals: an exclusive ac effect absent in static fields.
We report, for a nematic liquid crystal with a low conductivity anisotropy, an ac field generated transition from a uniformly planar to a periodically modulated director configuration with the wave vector parallel to the initial director. Significantly, with unblocked electrodes, this instability is not excited by dc fields. Additionally, in very low frequency square wave fields, it occurs transiently after each polarity reversal, vanishing completely during field constancy. The time of occurrence of maximum distortion after polarity reversal decreases exponentially with voltage. The time dependence of optical phase change during transient distortion is nearly Gaussian. The pattern threshold Vc is linear in sqrt[f], f denoting the frequency; the critical wave number qc of the modulation scales nearly linearly as sqrt[f] to a peak at approximately 50 Hz before falling slightly thereafter. The observed Vc(f) and qc(f) characteristics differ from the predictions of the standard model (SM). The instability may be interpreted as a special case of the Carr-Helfrich distortion suppressed in static fields due to weak charge focusing and strong charge injection. Its transient nature in the low frequency regime is suggestive of the possible role of gradient flexoelectric effect in its occurrence. The study includes measurement of certain elastic and viscosity parameters relevant to the application of the SM.


Intraperitoneal catheter leads to prolongation of the time to normalization of serum CA125 levels.
The intraperitoneal (IP) catheter has the potential to cause peritoneal irritation, which may contribute to an elevated CA125 level. We hypothesize that patients undergoing IP chemotherapy may have elevated CA125 values when compared with patients receiving intravenous (IV) chemotherapy. From February 2006 to July 2007, optimally debulked patients with stage III and stage IV ovarian carcinoma from a single institution were offered an outpatient IV/IP chemotherapy regimen modified from Gynecologic Oncology Group 172. They were matched to a cohort of similar patients who received IV paclitaxel and carboplatin. Demographic data and CA125 levels were collected before each cycle of chemotherapy and after the removal of the IP catheter. Statistical analysis was completed using a chi2 test with a significance level of P < 0.05. Fifty patients received the standard IV regimen, and 38 patients completed the modified IV/IP regimen. There was no statistical difference in the median CA125 values between the 2 groups during the treatment. After 6 cycles of therapy, 68.4% (26/38) of the IP cohort had a normal CA125 level before IP catheter removal compared with 78% (39/50) in the IV chemotherapy cohort (P = 0.44). After removal of the IP catheter, 86.8% (33/38) of the patients had a normal CA125 value (68.4% vs 86.8%, P = 0.049). After removal of the IP catheter, an additional 18.2% (7/38) of patients in the IP group had normalized their CA125 level. Because CA125 levels at the end of the treatment have prognostic significance, the role of the IP catheter in an elevated CA125 level must be considered.


Intrinsic radiolabeling of Titanium-45 using mesoporous silica nanoparticles.
Titanium-45 (45Ti) with a three-hour half-life (t1/2=3.08 h), low maximum positron energy and high positron emission branching ratio, is a suitable positron emission tomography (PET) isotope whose potential has not yet been fully explored. Complicated radiochemistry and rapid hydrolysis continue to be major challenges to the development of 45Ti compounds based on a traditional chelator-based radiolabeling strategy. In this study we introduced an intrinsic (or chelator-free) radiolabeling technique for the successful labeling of 45Ti using mesoporous silica nanoparticle (MSN). We synthesized uniform MSN with an average particle size of ∼150 nm in diameter. The intrinsic 45Ti-labeling was accomplished through strong interactions between 45Ti (hard Lewis acid) and hard oxygen donors (hard Lewis bases), the deprotonated silanol groups (-Si-O-) from the outer surface and inner meso-channels of MSN. In vivo tumor-targeted PET imaging of as-developed PEGylated [45Ti]MSN was further demonstrated in the 4T1 murine breast tumor-bearing mice. This MSN-based intrinsic radiolabeling strategy could open up new possibilities and speed up the biomedical applications of 45Ti in the future.


On-Surface Azide-Alkyne Cycloaddition Reaction: Does It Click with Ruthenium Catalysts?
Owing to its simplicity, selectivity, high yield, and the absence of byproducts, the "click" azide-alkyne reaction is widely used in many areas. The reaction is usually catalyzed by copper(I), which selectively produces the 1,4-disubstituted 1,2,3-triazole regioisomer. Ruthenium-based catalysts were later developed to selectively produce the opposite regioselectivity─the 1,5-disubstituted 1,2,3-triazole isomer. Ruthenium-based catalysis, however, remains only tested for click reactions in solution, and the suitability of ruthenium catalysts for surface-based click reactions remains unknown. Also unknown are the electrical properties of the 1,4- and 1,5-regioisomers, and to measure them, both isomers need to be assembled on the electrode surface. Here, we test whether ruthenium catalysts can be used to catalyze surface azide-alkyne reactions to produce 1,5-disubstituted 1,2,3-triazole, and compare their electrochemical properties, in terms of surface coverages and electron transfer kinetics, to those of the compound formed by copper catalysis, 1,4-disubstituted 1,2,3-triazole isomer. Results show that ruthenium(II) complexes catalyze the click reaction on surfaces yielding the 1,5-disubstituted isomer, but the rate of the reaction is remarkably slower than that of the copper-catalyzed reaction, and this is related to the size of the catalyst involved as an intermediate in the reaction. The electron transfer rate constant (ket) for the ruthenium-catalyzed reaction is 30% of that measured for the copper-catalyzed 1,4-isomer. The lower conductivity of the 1,5-isomer is confirmed by performing nonequilibrium Green's function computations on relevant model systems. These findings demonstrate the feasibility of ruthenium-based catalysis of surface click reactions and point toward an electrical method for detecting the isomers of click reactions.


1,12-diazaperylene and 2,11-dialkylated-1,12-diazaperylene iridium(III) complexes [Ir(C^N)2(N^N)]PF6: new supramolecular assemblies.
A series of new monocationic iridium(III) complexes [Ir(C^N)(2)(N^N)]PF(6) with "large-surface"α,α'-diimin ligands N^N (dap = 1,12-diazaperylene, dmedap = 2,11-dimethyl-1,12-diazaperylene, dipdap = 2,11-diisopropyl-1,12-diazaperylene) and different cyclometalating ligands C^N (piq = 1-phenylisoquinoline, bzq = benzo[h]quinoline, ppz = 1-phenylpyrazole, thpy = 2-(2-thienyl)pyridine, ppy = 2-phenylpyridine, meppy = 2-(4-methylphenyl)pyridine, dfppy = 2-(2,4-difluorophenyl)pyridine) were synthesized. The solid structures of the complexes [Ir(piq)(2)(dap)]PF(6), [Ir(bzq)(2)(dap)]PF(6), [Ir(ppy)(2)(dipdap)]PF(6), [Ir(piq)(2)(dmedap)]PF(6), [Ir(ppy)(2)(dap)]PF(6) and [Ir(ppz)(2)(dap)]PF(6) are reported. In [Ir(piq)(2)(dap)]PF(6), the dap ligand and one of the piq ligands of each cationic complex are involved in π-π stacking interactions forming supramolecular channels running along the crystallographic c axis. In the crystalline [Ir(bzq)(2)(dap)]PF(6)π-π stacking interactions between the metal complexes lead to the formation of a 2D layer structure. In addition, CH-π interactions were found in all compounds, which are what stabilizes the solid structure. In particular, a significant number of them were found in [Ir(piq)(2)(dap)]PF(6) and [Ir(bzq)(2)(dap)]PF(6). The crystal structures of [Ir(ppy)(2)(dipdap)]PF(6) and [Ir(ppy)(2)(dmedap)]PF(6) are also presented, being the first examples of bis-cyclometalated iridium(iii) complexes with phenanthroline-type α,α'-diimin ligands bearing bulky alkyl groups in the neighbourhood of the N-donor atoms. These ligands implicate a distorted octahedral coordination geometry that in turn destabilized the Ir-N(N^N) bonds. The new iridium(iii) complexes are not luminescent. All compounds show an electrochemically irreversible anodic peak between 1.15 and 1.58 V, which is influenced by the different cyclometalated ligands. All of the new complexes show two reversible successive one-electron "large-surface" ligand-centred reductions around -0.70 V and -1.30 V. Electrospray ionisation mass spectrometry (ESI-MS) and collision induced decomposition (CID) measurements were used to investigate the stability of the new complexes. Thereby, the stability agreed well with the order of the Ir-N(N^N) bond lengths.


Nonglycolytic acidification of murine radiation-induced fibrosarcoma 1 tumor via 3-O-methyl-D-glucose monitored by 1H, 2H, 13C, and 31P nuclear magnetic resonance spectroscopy.
The effects of 3-O-methyl-D-glucose (3-OMG) on subcutaneously implanted murine radiation-induced fibrosarcoma 1 tumor were examined with 2H, 13C, and 31P nuclear magnetic resonance (NMR) in situ. Using 31P NMR, changes in tumor high-energy phosphate metabolism were monitored for 2.5 h after i.p. administration of 3-OMG (8.1 g/kg body weight); tumor pH decreased by a mean maximum of 0.52 +/- 0.05 (SE) (n = 10), [PCr] decreased by 54%, [NTP] decreased by 35%, and [Pi] increased by 36%. Tumor blood flow, as measured by 2H NMR monitoring of D2O washout kinetics, decreased by 40% at 1 h and by 47% at 2 h after 3-OMG injection (n = 4). This substantial tumor acidification (pH decrease much greater than 0.1), expected to require a glycolytic substrate (Hwang et al., Cancer Res., 51: 3108-3118, 1991), is surprising in light of the previously documented metabolically inert nature of 3-OMG. In situ 13C NMR spectroscopy, following [6-13C]3-OMG i.p. injection, examined the possibility of the glycolytic metabolism of 3-OMG. However, only the C-6 resonance of 3-OMG was detected (n = 6); no resonances from [6-13C]3-OMG-6-phosphate or [3-13C]lactate were observed. These results confirmed that 3-OMG was not metabolized in radiation-induced fibrosarcoma 1 tumor. At the completion of the in situ 13C NMR experiments, tumors were freeze clamped, and perchloric acid extraction was performed. High-resolution 1H NMR measurement of lactate concentrations showed no statistically significant difference in control tumor extracts (from mice not receiving i.p. injection; n = 5) and in tumor extracts from mice administered i.p. [6-13C]3-OMG (n = 5), indicating that there was no significant increase in lactate level in the tumor extracts from mice administered i.p. 3-OMG due to increased plasma glucose concentration. The results of these 1H and 13C NMR studies indicated that the radiation-induced fibrosarcoma 1 tumor acidification caused by i.p. administration of 3-OMG was not due to a direct (3-OMG----lactate) or an indirect (systemic glucose----lactate) increase in tumor lactic acid levels.


NSAIDs: behind the mechanisms of action.
Non-steroidal anti-inflammatory drugs (NSAIDs) are a heterogeneous group of compounds. These heterogeneous agents have a similar therapeutic action for the treatment of pain, fever and inflammation. The major mechanism of action of NSAIDs is the inhibition of cyclooxygenase (COX), the enzyme catalysing the synthesis of prostaglandins (PGs). Appropriate and effective treatment for migraine depends upon an accurate diagnosis. The goals of treatment are amelioration of the symptoms of an acute attack and prevention of further attacks.


Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor.
Bone morphogenetic protein (BMP) receptors signal by phosphorylating Smad1, which then associates with Smad4; this complex moves into the nucleus and activates transcription. Here we report the existence of a natural inhibitor of this process, Smad6, a longer version of the previously reported JV15-1. In Xenopus embryos and in mammalian cells, Smad6 specifically blocks signaling by the BMP/Smad1 pathway. Smad6 inhibits BMP/Smad1 signaling without interfering with receptor-mediated phosphorylation of Smad1. Smad6 specifically competes with Smad4 for binding to receptor-activated Smad1, yielding an apparently inactive Smad1-Smad6 complex. Therefore, Smad6 selectively antagonizes BMP-activated Smad1 by acting as a Smad4 decoy.


Multivalent design of the monoclonal SynO2 antibody improves binding strength to soluble α-Synuclein aggregates.
Soluble aggregates are reported to be the most neurotoxic species of α-Synuclein (αSyn) in Parkinson's disease (PD) and hence are a promising target for diagnosis and treatment of PD. However, the predominantly intracellular location of αSyn limits its accessibility, especially for antibody-based molecules and prompts the need for exceptionally strong soluble αSyn aggregate binders to enhance their sensitivity and efficacy for targeting the extracellular αSyn pool. In this study, we have created the multivalent antibodies TetraSynO2 and HexaSynO2, derived from the αSyn oligomer-specific antibody SynO2, to increase avidity binding to soluble αSyn aggregate species through more binding sites in close proximity. The multivalency was achieved through recombinant fusion of single-chain variable fragments of SynO2 to the antibodies' original N-termini. Our ELISA results indicated a 20-fold increased binding strength of the multivalent formats to αSyn aggregates, while binding to αSyn monomers and unspecific binding to amyloid β protofibrils remained low. Kinetic analysis using LigandTracer revealed that only 80% of SynO2 bound bivalently to soluble αSyn aggregates, whereas the proportion of TetraSynO2 and HexaSynO2 binding bi- or multivalently to soluble αSyn aggregates was increased to ~ 95% and 100%, respectively. The overall improved binding strength of TetraSynO2 and HexaSynO2 implies great potential for immunotherapeutic and diagnostic applications with targets of limited accessibility, like extracellular αSyn aggregates. The ability of the multivalent antibodies to bind a wider range of αSyn aggregate species, which are not targetable by conventional bivalent antibodies, thus could allow for an earlier and more effective intervention in the progression of PD.


Nitrogen-Enriched Cr1-xAlxN Multilayer-Like Coatings Manufactured by Dynamic Glancing Angle Direct Current Magnetron Sputtering.
Multilayer-like CrN and Cr1-xAlxN coatings with different Al contents were deposited onto a stainless steel substrate using dynamic glancing angle deposition direct current magnetron sputtering (DGLAD dcMS) in a N rich atmosphere to understand the role of Al on the growth of the films and mechanical properties of the nitrides with a multilayer architecture. Chemical analysis by means of energy dispersive analysis (EDS) and glow discharge optical emission spectroscopy (GDOES) depth profiling revealed that while CrN samples were close to stoichiometric, the Cr1-xAlxN coatings presented excess N between 70 and 80% at. An expressive change in texture was observed as the CrN coating changed its preferred orientation from (111) to (200) with the addition of Al, followed by a modification in morphology from grains with faceted pyramidal tops in CrN to dome-shaped grains in Cr1-xAlxN coatings. Multilayer-like nanostructures of corrugated grains were produced with a periodicity of approximately 30 nm using dynamic glancing angle deposition. The deposition rate was drastically reduced with an increase of Al, meanwhile, the best mechanical performance was achieved for the coating with a higher content of Al, with hardness up to 27 GPa and a higher value of maximum resistance to plastic deformation.


Sex hormones, the stool microbiome, and subclinical atherosclerosis in women with and without HIV.
The cardio-protective roles of endogenous estrogens may be particularly important in women with HIV, who have reduced estrogen exposure and elevated cardiovascular disease risk. The gut microbiome metabolically interacts with sex hormones, but little is known regarding how such interplay may impact cardiovascular risk. Among 197 post-menopausal women in the Women's Interagency HIV Study, we measured 15 sex hormones in serum and assessed the gut microbiome in stool. B-mode ultrasound was used to determine presence of carotid artery plaque in a subset (n = 134). We examined associations of (1) sex hormones and stool microbiome, (2) sex hormones and plaque, and (3) sex hormone-related stool microbiota and plaque, adjusting for potential confounders. Participant median age was 58 years and the majority were living with HIV (81%). Sex hormones (estrogens, androgens, and adrenal precursors) were associated with stool microbiome diversity and specific species, similarly in women with and without HIV. For example, estrogens were associated with higher diversity, higher abundance of species from Alistipes, Collinsella, Erysipelotrichia, and Clostridia, and higher abundance of microbial β-glucuronidase and aryl-sulfatase orthologs, which are involved in hormone metabolism. Several hormones were associated with lower odds of carotid artery plaque, including dihydrotestosterone, 3α-diol-17G, estradiol, and estrone. Exploratory mediation analysis suggested that estrone-related species, particularly from Collinsella, may mediate the protective association of estrone with plaque. Serum sex hormones are significant predictors of stool microbiome diversity and composition, likely due in part to metabolic interactions. The gut microbiome may play a role in estrogen-related cardiovascular protection.


[Persistence of the Salmonella enteritidis recombinant strain with expressed HBc antigen in mice and macrophage culture].
The behavior of S. enteritidis recombinant strain E-23/pKDNA(3.1) with HBc antigen expressed by the eukaryotic promoter (DNA vaccine) in the body of mice after their infection per rectum and in the culture of macrophages was studied. The expression of HBc was shown to lead to the loss of the capacity of salmonellae for persistence in parenteral lymphoid tissue and for inducing the formation of anti-HBc antibodies. The study of the interaction of salmonellae with the macrophage culture revealed that the synthesis of HBc antigen inhibited the intracellular multiplication of salmonellae.


Presence with purpose: attitudes of people with developmental disability towards health care students.
Early clinical encounters help medical and nursing students build professional competencies. However, there is a necessary emphasis on patient autonomy and appropriate consent. Although most individuals do not object to student involvement in clinical encounters, there are occasions when personal preference and health care education conflict. Many studies have evaluated patient attitudes towards students across a variety of specialties. The purpose of this study was to identify the attitudes, comfort level and preferences of individuals with developmental disability (DD) towards the presence and involvement of medical and nursing students during clinical encounters. Adults with DD across the Hamilton-Niagara region were invited to participate. Focus groups were moderated by two students with a health care facilitator and physician-educator. Participants were provided with focus group questions in advance and encouraged to bring communication aids or care providers. Data were analysed for emerging themes by two independent reviewers, who then compared results. Twenty-two individuals participated. A wide range of opinions were expressed. Some participants were positively disposed towards students and perceived better care and improved communication with the health care team. Others were indifferent to students in a clinical setting. The final group was opposed to the presence of health care students, expressing confusion over their role and purpose, uneasiness with deviation from the norm, and concerns about confidentiality. Informative introductions with confidentiality statements and the presence of a supervising clinician were seen as helpful. People with DD are affected by above-average health care needs. Their input into health care planning has been limited. Their opinions on health care learners varied considerably. Themes relating to attitudes, comfort and preferences about student involvement provide impetus for health care training practices that promote person-centred approaches and improvements to the quality of care received by people with DD.


A cross-sectional survey of respiratory and general health outcomes among semiconductor industry workers.
As part of the Semiconductor Health Study, we performed a cross-sectional survey to assess prevalence of specific nonreproductive health outcomes and their association with occupational exposures. A total of 3,175 persons from eight manufacturing sites across the U.S. completed a health and work questionnaire (78% participation rate). After adjusting for confounders, responses from fabrication room (fab) workers indicated a greater risk than those of nonfab workers for upper respiratory symptoms (relative risk [RR] = 1.08; 95% confidence interval [CI] = 1.03-1.13); a dose-response effect with hours per day spent in fabs was observed. Fab workers also had greater prevalence for persistent wheezing (RR = 1.82; 95% CI = 1.15-2.87), dermatitis within the past year (RR = 1.19; 95% CI = 1.04-1.35), and alopecia (RR = 1.73; 95% CI = 1.16-2.54). Female sex, a somatization index score, and smoking were important nonoccupational covariates. Increased respiratory symptoms may result from occupational exposures in fabs; further research is needed to identify causal agents and develop prevention strategies.


Acetic acid bacteria spoilage of bottled red wine -- a review.
Acetic acid bacteria (AAB) are ubiquitous organisms that are well adapted to sugar and ethanol rich environments. This family of Gram-positive bacteria are well known for their ability to produce acetic acid, the main constituent in vinegar. The oxidation of ethanol through acetaldehyde to acetic acid is well understood and characterised. AAB form part of the complex natural microbial flora of grapes and wine, however their presence is less desirable than the lactic acid bacteria and yeast. Even though AAB were described by Pasteur in the 1850s, wine associated AAB are still difficult to cultivate on artificial laboratory media and until more recently, their taxonomy has not been well characterised. Wine is at most risk of spoilage during production and the presence of these strictly aerobic bacteria in grape must and during wine maturation can be controlled by eliminating, or at least limiting oxygen, an essential growth factor. However, a new risk, spoilage of wine by AAB after packaging, has only recently been reported. As wine is not always sterile filtered prior to bottling, especially red wine, it often has a small resident bacterial population (<10(3) cfu/mL), which under conducive conditions might proliferate. Bottled red wines, sealed with natural cork closures, and stored in a vertical upright position may develop spoilage by acetic acid bacteria. This spoilage is evident as a distinct deposit of bacterial biofilm in the neck of the bottle at the interface of the wine and the headspace of air, and is accompanied with vinegar, sherry, bruised apple, nutty, and solvent like off-aromas, depending on the degree of spoilage. This review focuses on the wine associated AAB species, the aroma and flavour changes in wine due to AAB metabolism, discusses the importance of oxygen ingress into the bottle and presents a hypothesis for the mechanism of spoilage of bottled red wine.


[Gastroenteritis and acute respiratory infections among children up to 5 years old in an area of Southeastern Brazil, 1986-1987, II--Diarrhea].
The decrease morbi-mortality gastroenteritis in is related to the factor responsible largely for the fall in infant mortality and mortality from communicable diseases in developing countries. Nevertheless, diarrhea is still a considerable public health problem in these countries, especially among children under 5 years old. To describe some aspects of the of gastroenteritis epidemiology among children up to 5 years old, resident in areas of S. Paulo county. A probabilistic sample of children up to 5 years old was studied (n = 468). The epidemiological survey was undertaken in five areas S. Paulo county (Brazil) from March 1986 to May 1987. Data were obtained through household interviews once a month over a year. During the follow-up 139 diarrhea episodes were registered, with a mean duration of 5.5 days. Twenty percent of the diarrhea events were followed by at least one other case in the household. The incidence of gastroenteritis was 2.78 episodes per 100 children/month. The highest incidence affected the children of up to 2 years of age. In 46.1% of the gastroenteritis episodes medical assistance was not sought, the children were treated by their mothers or not at all: 51.8% of the diarrhea events were attended to by the primary health care service, and only 2.1% were attended to by a hospital. No child died as a consequence of diarrhea. Of the therapeutical interventions used the most frequent were oral rehydration (25.2%) and oral rehydration with antibiotics (11.5%). Various socio-economic and personal background factors such as living conditions, water supply, sewarage, coverage; family income per capita and prior history of frequent gastroenteritis were associated with a higher incidence of gastroenteritis. The results seen to reflect the tendency of morbi-mortality by gastroenteritis to decrease in S. Paulo county during the 1980's when hospital treatment of diarrhea presented a considerable reduction. This tendency must be observed closely, because it will influence the changes to be mode in the kind of demand for medical care.


How food controls aggression in Drosophila.
How animals use sensory information to weigh the risks vs. benefits of behavioral decisions remains poorly understood. Inter-male aggression is triggered when animals perceive both the presence of an appetitive resource, such as food or females, and of competing conspecific males. How such signals are detected and integrated to control the decision to fight is not clear. For instance, it is unclear whether food increases aggression directly, or as a secondary consequence of increased social interactions caused by attraction to food. Here we use the vinegar fly, Drosophila melanogaster, to investigate the manner by which food influences aggression. We show that food promotes aggression in flies, and that it does so independently of any effect on frequency of contact between males, increase in locomotor activity or general enhancement of social interactions. Importantly, the level of aggression depends on the absolute amount of food, rather than on its surface area or concentration. When food resources exceed a certain level, aggression is diminished, suggestive of reduced competition. Finally, we show that detection of sugar via Gr5a+ gustatory receptor neurons (GRNs) is necessary for food-promoted aggression. These data demonstrate that food exerts a specific effect to promote aggression in male flies, and that this effect is mediated, at least in part, by sweet-sensing GRNs.


Diagnosis and grading of gastritis by non-invasive optical analysis.
The precise identification of many diseases of the gastrointestinal tract requires the histological analysis of multiple biopsies of the lining mucosae, thus preventing an immediate diagnosis and the safe screening of the entire organ. To address these limitations, we developed a novel spectroscopic procedure for a real-time, non-invasive optical analysis of mucosae. We have used a fibre-optic probe that monitors light propagation through small tissue volumes to evaluate the antral and fundic mucosa of 51 patients that underwent gastroscopy for symptoms of dyspepsia. Several optical coefficients were computed from the recorded light reflectance, and confronted to the diagnosis made by an expert gastroscopist at the time of the clinical examination. Both evaluations were then validated by comparison with the histological diagnosis of a pathologist who screened biopsies taken at the sites of the optical measurements. We report that the optical procedure discriminated normal and pathological gastric mucosae with a higher sensitivity and specificity than endoscopic diagnosis. We also show that the changes in light-scattering coefficient, which permitted the optical diagnosis of gastritis alterations, were indirectly correlated with the extent of inflammatory infiltration of the mucosa and detected mucosal alterations mild enough to escape endoscopic detection. The results show that, in a normal clinical setting, the optical in vivo analysis provided by our system detects alterations typical of gastritis, and allow for their graded scoring with a specificity and sensitivity that compare well with those of standard histology, while avoiding the invasiveness of the latter procedure. The method is adaptable to the screening of other types of lesions and mucosae and, hence, should prove useful in improving available diagnostic approaches.


PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3.
Prostate cancer antigen 3 (PCA3) is the most specific prostate cancer biomarker but its function remains unknown. Here we identify PRUNE2, a target protein-coding gene variant, which harbors the PCA3 locus, thereby classifying PCA3 as an antisense intronic long noncoding (lnc)RNA. We show that PCA3 controls PRUNE2 levels via a unique regulatory mechanism involving formation of a PRUNE2/PCA3 double-stranded RNA that undergoes adenosine deaminase acting on RNA (ADAR)-dependent adenosine-to-inosine RNA editing. PRUNE2 expression or silencing in prostate cancer cells decreased and increased cell proliferation, respectively. Moreover, PRUNE2 and PCA3 elicited opposite effects on tumor growth in immunodeficient tumor-bearing mice. Coregulation and RNA editing of PRUNE2 and PCA3 were confirmed in human prostate cancer specimens, supporting the medical relevance of our findings. These results establish PCA3 as a dominant-negative oncogene and PRUNE2 as an unrecognized tumor suppressor gene in human prostate cancer, and their regulatory axis represents a unique molecular target for diagnostic and therapeutic intervention.


Michigan system for opioid overdose surveillance.
Community rapid response may reduce opioid overdose harms, but is hindered by the lack of timely data. To address this need, we created and evaluated the Michigan system for opioid overdose surveillance (SOS). SOS integrates suspected fatal overdose data from Medical Examiners (MEs), and suspected non-fatal overdoses (proxied by naloxone administration) from the Michigan Emergency Medical Services (EMS) into a web-based dashboard that was developed with stakeholder feedback. Authorised stakeholders can view approximate incident locations and automated spatiotemporal data summaries, while the general public can view county-level summaries. Following Centers for Disease Control and Prevention (CDC) surveillance system evaluation guidelines, we assessed simplicity, flexibility, data quality, acceptability, sensitivity, positive value positive (PVP), representativeness, timeliness and stability of SOS. Data are usually integrated into SOS 1-day postincident, and the interface is updated weekly for debugging and new feature addition, suggesting high timeliness, stability and flexibility. Regarding representativeness, SOS data cover 100% of EMS-based naloxone adminstrations in Michigan, and receives suspected fatal overdoses from MEs covering 79.1% of Michigan's population, but misses those receiving naloxone from non-EMS. PVP of the suspected fatal overdose indicator is nearly 80% across MEs. Because SOS uses pre-existing data, added burden on MEs/EMS is minimal, leading to high acceptability; there are over 300 authorised SOS stakeholders (~6 new registrations/week) as of this writing, suggesting high user acceptability. Using a collaborative, cross-sector approach we created a timely opioid overdose surveillance system that is flexible, acceptable, and is reasonably accurate and complete. Lessons learnt can aid other jurisdictions in creating analogous systems.


Integration of the adeno-associated virus genome into cellular DNA in latently infected human Detroit 6 cells.
A clone of human cells (Detroit 6) latently infected by adeno-associated virus (AAV) has been characterized with regard to the status of the viral DNA. In both early (9 to 10) and late (118) passages of the clone, AAV-DNA was recombined with host DNA, at least in some cases as a head-to-tail tandem repeat, via the terminal sequences of the viral genome. However, it was not possible to distinguish between integration into chromosomal DNA and very large plasmids (< 20 x 10(6) molecular weight) which contain both viral and cellular DNA sequences. Although evidence for some modifications of the viral sequence was obtained, most of the integrated sequences appeared to be intact. In some cases sequences of undetermined origin separated adjacent copies of the viral genome. Free copies of the AAV genome were detectable in late passage cells, but not in early passage cells. The orientation of nucleotide sequences present in the free AAV DNA from late passage cells was indistinguishable from that of virion DNA. With the notable exception, the organization of the integrated AAV sequences as determined by restriction enzyme digestion remained constant with continued passage. Digestion with SmaI, which cleaves within the palindromic region of the terminal repetition in AAV DNA, produced reproducibly different patterns when early and late passage DNAs were compared. Several models for rescue of free copies of the genome from the integrated DNA are possible, all of which involve the terminal repetition.


Karnofsky Performance Scale and Neurological Assessment of Neuro-Oncology Scale as Early Predictor in Glioma.
Glioma is one of the most frequent and disabling primary brain tumour. Patients are not only dealing with survival, but also quality of life, which remains another major concern. Karnofsky Performance Scale (KPS) is one of the most commonly used scale to assess patients' quality of life. A recent scale, known as Neurological Assessment of Neuro-Oncology Scale, has surfaced to examine neurological disability caused by brain tumour. Previous study showed this scale to be superior to KPS in predicting survival. However, these scales have never been used to foresee functional scale improvement during disease progression. We sought to determine whether initial KPS and NANO Scale can predict functional scale improvement 2 months after surgery. Patients with glioma grade II-IV were included in the study. IDH mutation and MGMT methylation were tested. KPS and NANO scale were examined before surgery and 2 months after surgery. Favorable outcome (FO) was defined as improvement in functional scale 2 months after surgery. Patients initial functional scales were analyzed towards favorable outcome. Glioma WHO grade II, III and IV was found in 17 patients (36.2%), 3 patients (6.4%) and 27 patients (57.4%) respectively. Median KPS before and 2 months after surgery were 50 (30-80) and 60 (0-100), whereas median NANO scale before and 2 months after surgery were 5 (0-12) and 3 (0-12). Favorable outcome was found in 63.8% (KPS) and 78.7% (NANO Scale). Patients initial functional scales were significantly related to FO. Good initial functional scales are 4 to 5 times likely of having a favorable outcome 2 months after surgery.


Camp Raising Spirits: An Oncology Nursing Society Chapter Leadership Success Story .
Oncology Nursing Society (ONS) members share a unique passion for the people they serve and frequently commit to projects that make a difference. Camp Raising Spirits, a weekend retreat for adults with cancer, has made a difference in southwestern Pennsylvania for hundreds of people with cancer and their caregivers for 24 consecutive years. This article will describe how an ONS chapter capitalized on the leadership attributes of partnership, creativity, and commitment to sustain an important community service program. .


Microvascular tissue transfer in paediatric patients: analysis of 106 cases.
We report a series of 106 microvascular transplants performed in paediatric patients between 1973 and 1989. Eighty-eight percent of these flaps were successful. Two of the 13 failed flaps (1.9%) in this series were lost because of small vessel size. Otherwise, success rates (93% in the last 5 years) and complications were comparable to our adult cases. No growth-related complications were noted either in recipient or donor sites. We conclude that microvascular transplantation is a reliable procedure in children.


[Efficiency of antibiotics in children with acute respiratory infection complicated by pneumonia dependent on the acetylation type in the Far North regions].
Clinical characteristics of some diseases are defined by the phenotype of metabolic reactions, for example N-acetylation. Genetic polymorphism due to the activity of N-acetyltransferase (N-AT) is common in the majority of human populations. Consequently, persons with "slow" or "fast" acetylation phenotype should be identified. N-AT catalyzes acetylation of a number of medical products. Efficiency of pharmacotherapy is mostly associated with the specific features of medical products biotransformation. The processes of biotransformation with participation of acetyltransferase, monooxygenase or other ferment systems are under the gene control. The aim of the study was to characterize the features of the clinical course of acute respiratory infection complicated by pneumonia as dependent on the acetylation phenotype to predict the character of the disease and optimize the used antibiotic therapy among the native population (Yakut) and the arrived (Russian) in the Far North Regions (Sakha, Yakutia). 112 children with acute respiratory infections complicated by pneumonia and 49 practically healthy ones were examined. For the children with low N-AT activity (less than 30%) it was recommended to be treated with gentamicin which directly takes part in the acetylation and provides the antibiotic therapy efficiency in 80% of the cases. The use of cephalosporin antibiotics (beta-lactams), the metabolism of which is not directly connected with acetylation reactions provided the efficiency in 20% of the cases.


[Hypotheses on the origin of certain parasites on the Latin American continent].
The South American continent has been connected to Africa over millions of centuries. In prehistorical time, the filling of the Bering strait allowed passage on firm ground between Asia and North America. South American peopling has thus occurred from North America, through the Pacific sea and, from the 15th century A.C., through the Atlantic. Necator americanus was present in South America prior to the arrival of black slaves and its African origin is probably related to contacts between Africa and South America; the same applies to Leishmania donovani and Biom-Phalaria glabrata. Ankylostoma duodenale originates from Asia as well as Plasmodium falciparum which was brought by man at time of his migration. To the contrary, muco-cutaneous Leishmaniasis stem (or have a South American origin) from South America. Finally, it is difficult to understand for which reasons Loa loa has not established itself in South America as did Schistosoma mansoni.


Survival outcome after radiation therapy for patients with early cervical carcinoma undergoing inadequate primary surgery.
The aim of this study was to investigate the survival outcome after radiation therapy for patients with early cervical carcinoma undergoing inadequate primary surgery. A retrospective analysis of medical charts of all patients with stage IA2 to IIA carcinoma who were referred with inappropriate primary surgery and treated with radiation therapy was reviewed. The collected data include age, presenting symptoms, retrospective stage, lymph node status, histology type, type of surgery, baseline radiologic status before radiotherapy, details of radiation therapy, follow-up, and details of disease recurrence, disease-free survival, and overall survival (OS). Kaplan-Meier survival curves were used to show the OS and recurrence-free survival. A total of 32 patients were treated. The median age of the patients was 48.2 years, with a range of 27.6 to 79.2 years. Twenty-three patients had retrospective stage IB1, and 9 had stage IIA disease. The most common type of surgery (62.5%) was total abdominal hysterectomy with or without bilateral salpingo-oophorectomy. The pelvic lymph node dissection (PLND) status was not determined in 20 patients, 11 had PLND surgical assessment (2 were positive), and 1 had bulky PLND by computed tomographic scan.Baseline assessment showed that 14 patients had no residual disease, 11 had microscopic disease, and 7 had macroscopic disease. The follow-up ranged from 3.3 to 77.8 months, with a median of 24.3 months. Eleven patients developed disease recurrence, and all of them died of their disease. Two- and 5-year OS rates were 79% and 51.7%. Univariate analysis did not show a statistically significant effect of either the disease stage or residual disease survival. Survival outcome after radiation therapy for patients with early-stage cervical cancer undergoing inadequate surgery seems to be markedly worse than that for patients of comparable stage treated initially with radical radiation.


Diagnosis of occlusal caries using laser fluorescence versus conventional methods in permanent posterior teeth: a clinical study.
The purpose of this in vivo study was to compare three different caries detection methods [laser fluorescence (LFE), visual examination (VE), and radiological examination (RE)] for the detection of occlusal caries in permanent posterior teeth. Early diagnosis of caries is critical in the management of dental caries. Two examiners assessed the occlusal surfaces of 217 teeth by visual, radiographic, and laser fluorescence (DIAGNOdent Pen) examination methods. After a 1 week interval, randomly selected patients were recalled. Each measurement was repeated by two examiners before the cases were selected for operative intervention to classify lesion depths. Statistical analysis of the data was performed using SPSS and Stata IC. The intra- and inter-examiner reliabilities and reproducibilities of the VE, RE, and LFE were calculated using Cohen's κ statistics. The sensitivities and specificities were plotted in receiver operating characteristic curves. The differences between LFE scores were analyzed using the nonparametric Mann-Whitney U and Wilcoxon tests (α=0.05). The VE method exhibited the highest sensitivity, accuracy, and κ values among the diagnostic groups in terms of inter-examiner agreement. With regard to the sensitivity, specificity, and likelihood ratios for the two examiners, significant differences were found between sensitivity and specificity for examiner 1, whereas no statistically significant differences were noted between sensitivity and specificity for examiner 2 for the LFE scores. The DIAGNOdent pen is useful for the detection of dentinal caries of occlusal surfaces in permanent posterior teeth. Combination with other diagnostic conventional methods may enhance the reliability of this tool.


The effects of heavy resistance training and detraining on satellite cells in human skeletal muscles.
The aim of this study was to investigate the modulation of satellite cell content and myonuclear number following 30 and 90 days of resistance training and 3, 10, 30, 60 and 90 days of detraining. Muscle biopsies were obtained from the vastus lateralis of 15 young men (mean age: 24 years; range: 20-32 years). Satellite cells and myonuclei were studied on muscle cross-sections stained with a monoclonal antibody against CD56 and counterstained with Mayer's haematoxylin. Cell cycle markers CyclinD1 and p21 mRNA levels were determined by Northern blotting. Satellite cell content increased by 19% (P= 0.02) at 30 days and by 31% (P= 0.0003) at 90 days of training. Compared to pre-training values, the number of satellite cells remained significantly elevated at 3, 10 and 60 days but not at 90 days of detraining. The two cell cycle markers CyclinD1 and p21 mRNA significantly increased at 30 days of training. At 90 days of training, p21 was still elevated whereas CyclinD1 returned to pre-training values. In the detraining period, p21 and CyclinD1 levels were similar to the pre-training values. There were no significant alterations in the number of myonuclei following the training and the detraining periods. The fibre area controlled by each myonucleus gradually increased throughout the training period and returned to pre-training values during detraining. In conclusion, these results demonstrate the high plasticity of satellite cells in response to training and detraining stimuli and clearly show that moderate changes in the size of skeletal muscle fibres can be achieved without the addition of new myonuclei.


[Anatomic-topographic description of the stomach, small intestine, large intestine and their arteries of the greater mara (Dolichotis patagonum Desmarest 1820)].
The abdominal parts of the alimentary canal and the associated arteries from seven male and nine female maras are described. The mara possesses a stomach with a single cavity and a glandular mucosa lining. The large stomach is situated caudal of the liver at right-angles to the longitudinal body axis. The long jejunum is located on the left side of the body caudal of the stomach. The cecum has two teniae and numerous haustra which are proximal larger than distal. The smooth colon ascendens runs proximal parallel to the cecum and describes distal an U-shaped double-loop. The internal surface of the proximal part of the colon ascendens is characterized by two parallel mucosal ledges. Cecum and colon ascendens lie right caudal of the liver. The colon descendens is coiled and situated on the left body side. The A. gastrica sinistra and branches of the A. lienalis and the A. hepatica supply the stomach. The A. mesenterica cranialis which branches of separately from the A. coeliaca is a large and long vessel that supplies the major parts of the small intestine and the colon. The A. mesenterica caudalis supplies parts of the colon desendens and of the rectum.


Using DNA mechanics to predict in vitro nucleosome positions and formation energies.
In eukaryotic genomes, nucleosomes function to compact DNA and to regulate access to it both by simple physical occlusion and by providing the substrate for numerous covalent epigenetic tags. While competition with other DNA-binding factors and action of chromatin remodeling enzymes significantly affect nucleosome formation in vivo, nucleosome positions in vitro are determined by steric exclusion and sequence alone. We have developed a biophysical model, DNABEND, for the sequence dependence of DNA bending energies, and validated it against a collection of in vitro free energies of nucleosome formation and a set of in vitro nucleosome positions mapped at high resolution. We have also made a first ab initio prediction of nucleosomal DNA geometries, and checked its accuracy against the nucleosome crystal structure. We have used DNABEND to design both strong and weak histone- binding sequences, and measured the corresponding free energies of nucleosome formation. We find that DNABEND can successfully predict in vitro nucleosome positions and free energies, providing a physical explanation for the intrinsic sequence dependence of histone-DNA interactions.


Head-to-head comparison of basal stenosis resistance index, instantaneous wave-free ratio, and fractional flow reserve: diagnostic accuracy for stenosis-specific myocardial ischaemia.
We sought to compare the diagnostic accuracy of basal stenosis resistance index (BSR), instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR) for stenosis-specific myocardial ischaemia identified by means of a combined reference standard of myocardial perfusion scintigraphy and the hyperaemic stenosis resistance index. BSR and FFR were determined for 299 coronary stenoses, iFR was determined for 85 coronary stenoses (iFR cohort). The discriminative value for stenosis-specific myocardial ischaemia was compared by means of the area under the receiver operating characteristic (ROC) curves (AUC). Classification agreement with the reference standard was determined according to ROC curve-derived ischaemic cut-off values, as well as according to clinical cut-off values, equivalent to the 0.80 FFR cut-off. Across all stenoses, the discriminative value of BSR and FFR was equivalent (AUC: 0.90 and 0.91, respectively, p=0.46). In the iFR cohort, the discriminative value was equivalent for BSR, iFR, and FFR (AUC: 0.88, 0.84, and 0.88, respectively; p≥0.20 for all). At both ischaemic as well as clinical cut-off values, classification agreement with the reference standard was equivalent for BSR and FFR across all stenoses, as well as for BSR, iFR, and FFR in the iFR cohort. BSR, iFR, and FFR have equivalent diagnostic accuracy for the detection of ischaemia-generating coronary stenoses.


Advantages of new hemodialysis membranes and equipment.
Chronic kidney disease is characterized by the progressive retention of a number of compounds, several of which have the potential to cause cardiovascular damage. Many of these are difficult to remove by standard dialysis strategies. Removal of the larger middle molecules (mostly larger peptidic compounds) can be obtained by increasing dialyzer pore size and/or by applying convective strategies. For protein-bound solutes, convection (essentially hemodiafiltration) positively affects removal. The HEMO study demonstrated outcome superiority for the large-pore high-flux hemodialysis membranes in a number of subgroup analyses. Likewise, the Membrane Permeability Outcome study showed outcome superiority for high flux in patients with serum albumin <4 g/dl, the group for which the study had originally been designed. Apart from a small controlled trial, data suggesting superiority for convective strategies are all observational.


Consolidation therapy in ovarian cancer: a clinical update.
To evaluate current strategies under investigation for use as consolidation or maintenance treatment in patients with ovarian cancer. Patients with epithelial ovarian cancer often enter a complete remission after primary treatment. Many relapse, unfortunately, but some can return to remission after additional treatment. Outcomes can be improved by applying effective consolidation or maintenance approaches to patients in a complete primary or subsequent remission. A selective review of the literature is undertaken to consider strategies that are being or will likely be evaluated in randomized trials while we assess whether consolidation or maintenance will have a place in the treatment of patients with ovarian cancer. The application of extended standard cytotoxic agents has been generally disappointing, and no strategy applied in the first remission setting has prolonged overall survival. As treatment options move beyond classic chemotherapy to novel hormones, immune interventions, and biologic agents, the consolidation strategy is regaining interest. This is particularly attractive in that many of these agents have stable disease as best outcome, and this is most appropriate to evaluate in patients with minimal volume disease. A consideration of toxicity is paramount, and any strategy to be considered in an otherwise asymptomatic patient in remission must be well tolerated. In addition, patients in second or third complete remission are also being considered as an appropriate group in which to evaluate new agents. Numerous other phase 2 trials with novel agents not considered here are underway, and it is to be hoped that some will emerge as contenders for randomized trials. Participation in these trials remains a priority for patients who otherwise must pursue a difficult watch-and-wait strategy.


Is Clostridium difficile-associated infection a potentially zoonotic and foodborne disease?
Clostridium difficile has received much attention in recent years because of the increased incidence and severity of nosocomial disease caused by this organism, but C. difficile-associated disease has also been reported in the community, and C. difficile is an emerging pathogen in animals. Early typing comparisons did not identify animals as an important source for human infection, but recent reports have shown a marked overlap between isolates from calves and humans, including two of the predominant outbreak types, 027 and 017. C. difficile has also been found in retail meat samples, suggesting that food could be involved in the transmission of C. difficile from animals to humans.