Chronic orbital and calvarial fungal infection with Apophysomyces variabilis in an immunocompetent patient.
Apophysomyces is a rare fungal organism causing rhino-orbito-cerebral mycotic infections with high morbidity and mortality, typically in immunocompetent individuals. Several cases of Apophysomyces elegans orbital disease have been reported. Herein, we report a case of Apophysomyces variabilis infection involving the orbit, sinuses, and calvarium in an immunocompetent 74-year-old woman, with a review of the literature. Unlike prior cases of A. elegans classic rhino-orbito-cerebral infection, our case included diffuse calvarial lytic lesions and overlying soft tissue nodules, but without parenchymal intracranial involvement. There was radiographic and clinical evidence of infarction of the orbital contents and cavernous sinus thrombosis. Anastomoses between the superior orbital (ophthalmic) vein and diploic veins of the calvarium are believed to be primarily responsible for the unusual mode of spread on the extradural surface of the brain. Although the patient stabilized without definitive surgical intervention, her disease slowly and intermittently progressed for over a year after presentation, requiring multiple courses of antifungal treatment.


The Nazi! accusation and current US proposals.
In contemporary ethical discourse generally, and in discussions concerning the legalization of physician-assisted suicide (PAS) and voluntary active euthanasia (VAE) specifically, recourse is sometimes had to the Nazi! accusation. Some disputants charge that such practices are or will become equivalent to the Nazi 'euthanasia' program in which over 73,000 handicapped children and adults were killed without consent. This paper reflects on the circumstances that lead to the use of this charge and offers reasons for putting the Nazi! charge aside in contemporary discussions of PAS and VAE. A number of the philosophical presuppositions common to both the Nazi 'euthanasia' program and the currently proposed practices of PAS and VAE are examined. Noting that racist ideology and violent coercion characterized the Nazi program, the paper concludes with a cautionary consideration of the current circumstances that would specify PAS and VAE in the US.


Protective Effect of Astragaloside IV against Cadmium-Induced Damage on Mouse Renal Podocytes (MPC5).
In this study, we investigated the protective effect of Astragaloside IV (Ast) on mouse podocytes and its possible mechanism of action by constructing a cadmium-induced mouse renal podocytes model. We investigated the effects of cadmium (Cd) toxicity on cell number, morphology, the mitochondrial status of subcellular organelles, protein and gene levels, and the protective effects of Ast by constructing a model of Cd-induced damage to mouse renal podocytes (MPC5) and giving Ast protection at the same time. The results showed that exposure of MPC5 cells to CdCl2 culture medium containing 6.25 μM concentration acted with low cell mortality, but the mortality of MPC5 cells increased with the prolongation of cadmium exposure time. Given Ast, the death rate in the low dose group (12.5 μM) was significantly reduced, while the death rate in the medium dose group (25 μM) was extremely significantly reduced. In comparison to the control group, the Cd-exposed group exhibited a significant increase of 166.7% in malondialdehyde (MDA) content and a significant decrease of 17.1% in SOD activity. The mitochondrial membrane potential was also reduced to varying degrees. However, in the Ast-protected group compared to the Cd-exposed group, the MDA content significantly decreased by 20.8%, the SOD activity decreased by 7.14%, and the mitochondrial membrane potential showed a significant increase. Fluorescence staining of mitochondrial membrane potential indicated that Cd exposure caused mitochondrial apoptosis. In the 12-h cadmium-exposed group, the protein expression of Nephrin in mice significantly decreased by 33.4%. However, the expression of the Desmin protein significantly increased by 67.8%, and the expression of the autophagy protein LC3-II significantly increased by 55.5%. Meanwhile, the expression of PINK1, a mitochondrial autophagy pathway protein, was significantly increased in the 12 h and 24 h cadmium exposure groups. The mRNA level of PINK1 was significantly increased, and that of Parkin was decreased in the 48 h cadmium exposure group. Compared to the Cd-exposed group, the Ast group showed more significant improvements in the expression of podocyte structure, functional proteins, and mitochondrial autophagy pathway proteins. The immunological assay of mitochondrial autophagic pathway proteins further indicated that Cd-induced damage to MPC5 cells might be associated with the dysregulation of mitochondrial autophagy.


Impact of Admission White Blood Cell Count on Short- and Long-term Mortality in Patients With Type A Acute Aortic Dissection: An Observational Study.
Studies have shown inflammation is involved in the development of acute aortic dissection (AAD). The hypothesis that white blood cell count (WBCc) on admission may have an impact on the short- and long-term outcomes of type A AAD was tested in a large-scale, prospective observational cohort study.From 2008 to 2010, a total of 570 consecutive patients with type A AAD in Fuwai hospital were enrolled and were followed up. Baseline characteristics and WBCc on admission were collected. The primary outcomes were 30-day and long-term all-cause mortality.During a median of 1.89 years of follow-up, the 30-day and long-term all-cause mortality were 10.7% and 6.5%, respectively. Univariate Cox regression analysis identified admission WBCc as an independent predictor of 30-day mortality when considered as a continuous variable or as a categorical variable using the cutoff of 11.0 × 10 cells/L (all P < 0.05). After adjustment for age, sex, C-reactive protein, D-dimer, and surgical intervention, elevated admission WBCc (>11.0 × 10 cells/L) remained an independent predictor of 30-day mortality of AAD (hazard ratio = 3.31, 95% confidence interval 1.38-7.93, P = 0.007). No impact of admission WBCc was observed on the long-term all-cause mortality.In conclusion, elevated admission WBCc may be valuable as a predictor of 30-day mortality, and may be useful in the risk stratification of type A AAD during hospitalization.


RSV-hRV co-infection is a risk factor for recurrent bronchial obstruction and early sensitization 3 years after bronchiolitis.
To assess risk factors of recurrent bronchial obstruction and allergic sensitization 3 years after an episode of acute bronchiolitis, whether after ambulatory care treatment or hospitalization. A monocentric prospective longitudinal study including infants aged under 1 year with acute bronchiolitis was performed, with clinical (severity score), biological (serum Krebs von den Lungen 6 antigen), and viral (14 virus by naso-pharyngeal suction detection) assessments. Follow-up included a quaterly telephone interview, and a final clinical examination at 3 years. Biological markers of atopy were also measured in peripheral blood, including specific IgEs towards aero- and food allergens. Complete data were available for 154 children. 46.8% of them had recurrent wheezing (RW). No difference was found according to initial severity, care at home or in the hospital, respiratory virus involved, or existence of co-infection. A familial history of atopy was identified as a risk factor for recurrent bronchial obstruction (60% for RW infants versus 39%, P = 0.02), as living in an apartment (35% versus 15%, P = 0.002). 18.6% of the infants were sensitized, with 48.1% of them sensitized to aeroallergens and 81.5% to food allergens. Multivariate analysis confirmed that a familial history of atopy (P = 0.02) and initial co-infection RSV-hRV (P = 0.02) were correlated with the risk of sensitization to aeroallergens at 3 years. Familial history of atopy and RSV-hRV co-infection are risk factors for recurrent bronchial obstruction and sensitization.


Locating missing water molecules in protein cavities by the three-dimensional reference interaction site model theory of molecular solvation.
Water molecules confined in protein cavities are of great importance in understanding the protein structure and functions. However, it is a nontrivial task to locate such water molecules in protein by the ordinary molecular simulation and modeling techniques as well as experimental methods. The present study proves that the three-dimensional reference interaction site model (3D-RISM) theory, a recently developed statistical-mechanical theory of molecular solvation, has an outstanding advantage in locating such water molecules. In this paper, we demonstrate that the 3D-RISM theory is able to reproduce the structure and the number of water molecules in cavities of hen egg-white lysozyme observed commonly in the X-ray structures of different resolutions and conditions. Furthermore, we show that the theory successfully identified a water molecule in a cavity, the existence of which has been ambiguous even from the X-ray results. In contrast, we confirmed that molecular dynamics simulation is helpless at present to find such water molecules because the results substantially depend on the initial coordinates of water molecules. Possible applications of the theory to problems in the fields of biochemistry and biophysics are also discussed.


Chirped-pulse generation from optical parametric oscillators with an aperiodic quasi-phase-matching crystal.
We describe chirped-pulse generation from an optical parametric oscillator using an aperiodic quasi-phase-matching crystal as the gain medium. We examine the pulse formation dynamics, and reveal that the excitation of chirped-pulse oscillation is assisted by the position-dependent conversion-wavelength and the pump-to-signal temporal walk-off along the gain medium. Stable oscillation is confirmed by numerical simulations and experimental demonstrations. In a preliminary experiment, we obtained a signal wave covering 1293-1734 nm and an idler wave covering 2.9-5.0 µm from an oscillator based on a 2-mm-long aperiodically poled ${{\rm LiNbO}_3}$LiNbO3 crystal. These results represent a new, to the best of our knowledge, pulse formation mechanism inside a nonlinear oscillator, which is promising for generating light pulses with very wide instantaneous bandwidth and at arbitrary wavelengths.


S-adenosyl-L-methionine (SAMe) for the treatment of acetaminophen toxicity in a dog.
An 8-month-old, spayed female Shetland sheepdog presented 48 hours after ingesting acetaminophen (1 gm/kg body weight). On presentation, the dog was laterally recumbent and hypovolemic. The dog had brown mucous membranes, severe Heinz-body hemolytic anemia, bleeding tendencies, and a red blood cell (RBC) glutathione (GSH) concentration that was 10% of reference values, despite a regenerative erythroid response. Treatment with s-adenosyl-l-methionine (SAMe) as a GSH donor successfully rescued this dog, despite the animal's late presentation after drug ingestion. A loading dose (40 mg/kg body weight) of a stable SAMe salt per os was followed by a maintenance dose (20 mg/kg body weight) sid for 7 days. Additional therapeutic interventions included an intravenous (i.v.) infusion of one unit of packed RBCs (on admission), i.v. fluid support (3 days), and famotidine (7 days) to reduce gastric acidity. Sequential assessment of RBC GSH concentrations and RBC morphology documented response to antidote administration within 72 hours. This case suggests that SAMe may provide a therapeutic option for treatment of acetaminophen toxicosis in dogs capable of retaining an orally administered antidote and maintaining adequate hepatic function for metabolism of SAMe to its thiol substrates.


Behavior-related modulation of substantia nigra pars reticulata neurons in rats performing a conditioned reinforcement task.
Motor-control models of basal ganglia function have emphasized disinhibition through reduction of tonic, inhibitory output. Although these models have shed important light on basal ganglia operations, evidence emerging from electrophysiological studies of behaving primates suggests that disinhibition alone may not adequately explain the role of the basal ganglia in movement. To assess this role in the rat, the most frequently used subject in studies of basal ganglia function, we recorded neuronal activity in the primary output nucleus, the substantia nigra pars reticulata, during an operant task. After rats were trained to nosepoke into an illuminated hole for access to a 10% sucrose solution delivered through a spout, single- and multiple-unit activity was recorded during 60-120 nosepoke trials. Compared to the period 60 s before the start of the first trial in the task, 110 of 225 reticulata units increased firing >200% while 17 of 225 decreased to 40% of baseline. Of these 225 units, >60% responded coincident with specific task events such as nosepokes and spout licking. Most nosepoke-responsive units showed either excitation (>50%) or a combination of excitation and inhibition (>25%) rather than inhibition alone (>20%). Increases in firing were also common during approach and licking at the spout, with inhibitions alone comprising 30% of responses. In some units, there was evidence of reward-related responding, with changes occurring in anticipation of reward delivery or during the delivery of sucrose, but not the persistent licking that continued for several seconds after its offset. While 70% of units responded during both nosepokes and spout licking, changes in firing were typically unique depending on the motor behavior required (i.e. nosepoking vs. licking). Our results, which indicate a prominent role for increases in nigra reticulata activity during movement, add to growing evidence that although inhibitions may allow desired motor responses to emerge, excitations may help shape behavioral output by suppressing competing motor programs.


[Which time constant of left ventricular relaxation is the most sensitive measure in acute myocardial ischemia?].
To investigate which time constant of isovolumic left ventricular pressure (LVP) decay is the most sensitive measure in acute myocardial ischemia, the time constant of isovolumic relaxation (IR) was calculated by two different models, the semilogarithmic model assuming a zero of LVP decline (TL) and an exponential model (Texp) with an asymptote (extrapolated baseline pressure to which LVP would fall if decay continued indefinitely), in 10 patients before and during ergonovine-induced vasospastic angina. Two time constants were derived from the exponential method as the times for LVP at peak negative dP/dt to decline by 1/e (Texp (1/e)) and by one half (Texp (1/2)). Three changes in LVP during isovolumic relaxation were analyzed and fitted to the two models described above: the LVP from the peak negative dP/dt 1) to when LVP fell to 5 mmHg above LV end-diastolic pressure (EDP), 2) until 40 msec had passed, and 3) to the LVP level 5 mmHg above LVEDP during coronary spasm. There were significant increases in TL, Texp (1/e) and Texp (1/2) in each period of the LVP during vasospastic angina. However, no significant change in Texp or asymptote was observed during angina. We concluded that TL measured by the semilogarithmic model assuming a zero of LVP decline and Texp (1/e) or Texp (1/2) derived from the exponential model are adequately sensitive for detecting acute myocardial ischemia due to coronary spasm.


Language Mediated Concept Activation in Bilingual Memory Facilitates Cognitive Flexibility.
This is the first attempt of empirical investigation of language mediated concept activation (LMCA) in bilingual memory as a cognitive mechanism facilitating divergent thinking. Russian-English bilingual and Russian monolingual college students were tested on a battery of tests including among others Abbreviated Torrance Tests for Adults assessing divergent thinking traits and translingual priming (TLP) test assessing the LMCA. The latter was designed as a lexical decision priming test, in which a prime and a target were not related in Russian (language of testing), but were related through their translation equivalents in English (spoken only by bilinguals). Bilinguals outperformed their monolingual counterparts on divergent thinking trait of cognitive flexibility, and bilinguals' performance on this trait could be explained by their TLP effect. Age of second language acquisition and proficiency in this language were found to relate to the TLP effect, and therefore were proposed to influence the directionality and strength of connections in bilingual memory.


Psychometric properties of the Patient Assessment of Chronic Illness Care measure (PACIC-5A) among patients with obesity.
The Patient Assessment of Chronic Illness Care (PACIC-5A) was developed to assess the satisfaction with patient-provider interaction based on the Chronic Care Model. The additional 5A approach (assess, advise, agree, assist, arrange) allows to score behavioral counseling. The aim of the study was to assess the psychometric properties of the German adaptation of the PACIC-5A questionnaire in a sample of general practitioners (GP) patients with obesity. Analyses were based on data from the study "Five A's counseling in weight management of obese patients in primary care: a cluster randomized controlled trial (INTERACT)". Data were collected via standardized questionnaires containing the 26-item version of the PACIC-5A questionnaire. A total of 117 patients with obesity were included in the analyses. Statistical procedures comprised descriptive analyses, the calculation of Cronbach's alpha, test-retest analyses and factor analyses in order to assess the psychometric properties including reliability and validity of the PACIC-5A. The patient's mean age was 43.4 years and the sample was mostly female (59%). Middle educational level was found for the majority (78%) and the mean Body Mass Index was 38.9 kg/m2. Descriptive analyses revealed a mean PACIC score of 2.33 and 5A sum score of 2.29. Notable floor effects were found. PACIC-5A showed high level of internal consistency (Cronbach's alphas > 0.9) and exploratory factor analyses resulted in a unidimensional structure. The results of this study provide evidence regarding the psychometric properties of the German version of the PACIC-5A used in a sample of GP patients with obesity and make an important contribution to the reliable and valid assessment of the patient-GP interaction with regard to obesity counseling in primary care.


Elongation by Escherichia coli RNA polymerase is blocked in vitro by a site-specific DNA binding protein.
As a means of determining how elongating RNA polymerase responds to a protein in its path, transcription has been carried out in vitro with the purified Escherichia coli enzyme on templates associated with a sequence-specific DNA binding protein. The major RNA species generated is the length expected from RNA polymerase which has transcribed to the position of the bound protein and is unable to elongate further. The binding proteins used are two mutants of the EcoRI endonuclease which are defective in cleavage function but retain high affinity for the wild-type recognition sequence (Wright, D. J., King, K., and Modrich, P. (1989) J. Biol. Chem. 264, 11816-11821). Blockage of RNA polymerase occurs on linear and circular templates and, although efficient with both proteins, is more effective for the EcoRI derivative with the slower dissociation rate. The protein-blocked transcription complexes are stable over time and remain in an active form, resuming elongation when the blocking protein is displaced by an increase in ionic strength. These paused ternary complexes, if treated with the termination factor rho, undergo release. The 3' ends of the blocked-length RNAs from DNAs of distinct sequences reveal that the ternary complexes are positioned at a constant distance from the protein block, 14 nucleotides upstream of the EcoRI recognition sequence. This information is combined with exonuclease III footprinting data to position the 3' end of the nascent RNA chain in the ternary complex quite near (approximately 7 nucleotides) the leading edge of RNA polymerase.


Bacterial production and secretion of water-insoluble fuel compounds from cellulose without the supplementation of cellulases.
Achieving economic biofuel production from cellulosic biomass will require significant cost reductions. Enzymatic degradation of cellulosic biomass and distillation of water-soluble fuel compounds substantially increase the cost of biofuel production. Consolidated bioprocessing is a strategy to circumvent expensive biofuel production steps. Clostridium thermocellum is a promising bacterium for consolidated bioprocessing because it does not require the supplementation of lignocellulose-degrading enzymes. To produce water-insoluble fuel compounds, C. thermocellum was engineered to express a fatty acyl-acyl carrier protein reductase and an aldehyde-deformylating oxygenase from Synechococcus elongatus PCC 7942. Expression of the aldehyde-deformylating oxygenase gene was clearly detected, whereas only slight expression of the fatty acyl-acyl carrier protein reductase gene was detected. Cells expressing the fatty acyl-acyl carrier protein reductase and the aldehyde-deformylating oxygenase accumulated fatty aldehydes (higher alcohol precursors). After cultivation with cellulose, the higher alcohols, decanol and dodecanol, were detected in the organic solvent phase of the culture broth, indicating that the strain secreted the higher alcohols. These results suggest that the engineered C. thermocellum strain, expressing fatty acyl-acyl carrier protein reductase and aldehyde-deformylating oxygenase genes, directly produces and secretes higher alcohols from cellulose without the supplementation of cellulases. The higher alcohols can be collected by phase separation.


Comment on "Cellular automata model simulating traffic interactions between on-ramp and main road".
In a recent study of traffic flow around on-ramp [R. Jiang, Q. S. Wu, and B. H. Wang, Phys. Rev. E 66, 036104 (2002)], two different types of phase diagrams are reported: four distinct regions are observed in the cases of v(max)>1, while only two regions are present in the case of v(max)=1. We point out that the characteristics of the phase diagram are totally dictated by the prescribed asymmetric rule of the on-ramp. In the congested phase (region IV), the configurations evolve as stable limit cycles, and are independent of v(max). The saturated currents can be obtained analytically.


RDBridge: a knowledge graph of rare diseases based on large-scale text mining.
Despite low prevalence, rare diseases affect 300 million people worldwide. Research on pathogenesis and drug development lags due to limited commercial potential, insufficient epidemiological data, and a dearth of publications. The unique characteristics of rare diseases, including limited annotated data, intricate processes for extracting pertinent entity relationships, and difficulties in standardizing data, represent challenges for text mining. We developed a rare disease data acquisition framework using text mining and knowledge graphs and constructed the most comprehensive rare disease knowledge graph to date, Rare Disease Bridge (RDBridge). RDBridge offers search functions for genes, potential drugs, pathways, literature, and medical imaging data that will support mechanistic research, drug development, diagnosis, and treatment for rare diseases. RDBridge is freely available at http://rdb.lifesynther.com/.


Functionalization of Fe3O4@SiO2 nanoparticles with Cu(i)-thiosemicarbazone complex as a robust and efficient heterogeneous nanocatalyst for N-arylation of N-heterocycles with aryl halides.
In this research, the functionalized silica-coated magnetite nanoparticles with Cu(i)-thiosemicarbazone complex (Fe3O4@SiO2-[CuL]) has been designed and synthesized as a magnetically retrievable nanocatalyst. Different techniques were employed to characterize the structure of Fe3O4@SiO2-[CuL] comprising FT-IR, FE-SEM, TEM, DLS, XRD, EDX, TGA, AAS, and VSM analysis. The catalytic performance of Fe3O4@SiO2-[CuL] was perused in Ullmann-type N-arylation of nucleobases, xanthines, and other N-heterocycles with diverse aryl halides which acquired the desired N-aryl products in good to excellent yields. Fe3O4@SiO2-[CuL] is a thermal and chemical stable, easy to prepare and recyclable, inexpensive, and ecofriendly catalyst that needs no additional additive or ligand as promoters. This catalyst could be separated without difficulty by a simple magnet and reused for at least seven sequential runs without a significant decline in its catalytic performance.


Biomarkers identification for acute myocardial infarction detection via weighted gene co-expression network analysis.
The study aimed to seek potential biomarkers for acute myocardial infarction (AMI) detection and treatment.The dataset GSE48060 was used, consisting of 52 peripheral blood samples (31 AMI samples and 21 normal controls). By limma package, differentially expressed genes (DEGs) between 2 kinds of samples were identified, followed by enrichment analysis, subpathway analysis, protein-protein interaction (PPI) network analysis, and transcription factor network (TFN) analysis. Weighted gene co-expression network analysis was used to further extract key modules relating to AMI, followed by enrichment and TFN analyses. Expression validation was performed via meta-analysis of 2 datasets, GSE22229 and GSE29111.A set of 428 DEGs in AMI were screened out, and the upregulated toll-like receptor (TLR) family genes (TLR1, TLR2, and TLR10) were enriched in wound response, immune response and inflammatory response functions, and downregulated genes (GBP5, CXCL5, GZMA, CCL5, and CCL4) were correlated with immune response. CCL5, GZMA, GZMB, TLR2, and formyl peptide receptor 1 (FPR1) were predicted as crucial nodes in the PPI network. Signal transducer and activator of transcription 1 (STAT1) was the key transcription factor (TF) with multiple targets. The grey module was highly related to AMI. Genes in this module were closely related to regulation of macrophage activation, and spermatogenic leucine zipper 1 (SPZ1) was identified as a TF. Expressions of TLR2 and FPR1 were confirmed via the integrated matrix.Several potential biomarkers for AMI detection were identified, such as GZMB, GBP5, FPR1, TLR2, STAT1, and SPZ1. They might exert their functions via regulation of immune and inflammation responses. Genes in grey module play significant roles in AMI via regulation of macrophage activation.


Sporangium Exposure and Spore Release in the Peruvian Maidenhair Fern (Adiantum peruvianum, Pteridaceae).
We investigated the different processes involved in spore liberation in the polypod fern Adiantum peruvianum (Pteridaceae). Sporangia are being produced on the undersides of so-called false indusia, which are situated at the abaxial surface of the pinnule margins, and become exposed by a desiccation-induced movement of these pinnule flaps. The complex folding kinematics and functional morphology of false indusia are being described, and we discuss scenarios of movement initiation and passive hydraulic actuation of these structures. High-speed cinematography allowed for analyses of fast sporangium motion and for tracking ejected spores. Separation and liberation of spores from the sporangia are induced by relaxation of the annulus (the 'throwing arm' of the sporangium catapult) and conservation of momentum generated during this process, which leads to sporangium bouncing. The ultra-lightweight spores travel through air with a maximum velocity of ~5 m s(-1), and a launch acceleration of ~6300 g is measured. In some cases, the whole sporangium, or parts of it, together with contained spores break away from the false indusium and are shed as a whole. Also, spores can stick together and form spore clumps. Both findings are discussed in the context of wind dispersal.


Urinary metabolites as biomarkers of acrylamide exposure in mice following dietary crisp bread administration or subcutaneous injection.
Heat-treated carbohydrate-rich foods may contain high levels of acrylamide (AA). Crisp bread is a significant dietary AA source in the Nordic countries. We studied whether urinary metabolites of AA could be candidate biomarkers of AA intake and internal dose in mice following dietary crisp bread administration or sc injection. The crisp bread was experimentally baked to contain three different concentrations of AA: 0.19, 1.02, and 2.65 mg/kg, giving dietary exposures to AA of 0.024 +/- 0.002, 0.14 +/- 0.02, and 0.29 +/- 0.04 mg/kg bodyweight (bw)/day (mean +/- SD), respectively. A linear relationship was found between dietary AA exposure and urinary AA metabolites. On average, 55% of the ingested dose was recovered as urinary AA metabolites, and the molar proportions between the urinary metabolites showed similar proportions for the different doses. Urine AA metabolites were measured after sc injection of AA at doses of 0.05, 0.5, 5, and 50 mg/kg bw, and the urinary recovery for the three lowest doses was 54%. With the highest dose, 80% was recovered in urine, and the changed pattern of urinary metabolites indicated saturation of the metabolic conversion of AA to glycidamide. These results indicate that urinary metabolites of AA are good biomarkers of AA intake and internal dose up to 5 mg/kg bw/day. After sc injection of [(14)C]AA, 92% of the radioactivity was found in the urine and 2% in feces, liver, blood, and intestinal content (6% was not detected), demonstrating that sc AA was highly systemically available, that the major part AA metabolites was excreted, and that a significant portion of urinary AA metabolites (most likely glyceramide) was not accounted for by the present analytical method. Since the urinary recovery of AA after crisp bread feeding and sc injection was practically identical, an indicative "bioavailability" of AA from crisp bread was suggested to be approximately complete.


Effects of short-term acid and aluminum exposure on the parr-smolt transformation in Atlantic salmon (Salmo salar): disruption of seawater tolerance and endocrine status.
Episodic acidification resulting in increased acidity and inorganic aluminum (Al(i)) is known to interfere with the parr-smolt transformation of Atlantic salmon (Salmo salar), and has been implicated as a possible cause of population decline. To determine the extent and mechanism(s) by which short-term acid/Al exposure compromises smolt development, Atlantic salmon smolts were exposed to either control (pH 6.7-6.9) or acid/Al (pH 5.4-6.3, 28-64 microgl(-1) Al(i)) conditions for 2 and 5 days, and impacts on freshwater (FW) ion regulation, seawater (SW) tolerance, plasma hormone levels and stress response were examined. Gill Al concentrations were elevated in all smolts exposed to acid/Al relative to controls confirming exposure to increased Al(i). There was no effect of acid/Al on plasma ion concentrations in FW however, smolts exposed to acid/Al followed by a 24h SW challenge exhibited greater plasma Cl(-) levels than controls, indicating reduced SW tolerance. Loss of SW tolerance was accompanied by reductions in gill Na(+),K(+)-ATPase (NKA) activity and Na(+),K(+),2Cl(-) (NKCC) cotransporter protein abundance. Acid/Al exposure resulted in decreased plasma insulin-like growth factor (IGF-I) and 3,3',5'-triiodo-l-thyronine (T(3)) levels, whereas no effect of treatment was seen on plasma cortisol, growth hormone (GH), or thyroxine (T(4)) levels. Acid/Al exposure resulted in increased hematocrit and plasma glucose levels in FW, but both returned to control levels after 24h in SW. The results indicate that smolt development and SW tolerance are compromised by short-term exposure to acid/Al in the absence of detectable impacts on FW ion regulation. Loss of SW tolerance during short-term acid/Al exposure likely results from reductions in gill NKA and NKCC, possibly mediated by decreases in plasma IGF-I and T(3).


Use of antiviral drugs to reduce household transmission of pandemic (H1N1) 2009, United Kingdom.
The United Kingdom implemented a containment strategy for pandemic (H1N1) 2009 through administering antiviral agents (AVs) to patients and their close contacts. This observational household cohort study describes the effect of AVs on household transmission. We followed 285 confirmed primary cases in 259 households with 761 contacts. At 2 weeks, the confirmed secondary attack rate (SAR) was 8.1% (62/761) and significantly higher in persons <16 years of age than in those >50 years of age (18.9% vs. 1.2%, p<0.001). Early (<48 hours) treatment of primary case-patients reduced SAR (4.5% vs. 10.6%, p = 0.003). The SAR in child contacts was 33.3% (10/30) when the primary contact was a woman and 2.9% (1/34) when the primary contact was a man (p = 0.010). Of 53 confirmed secondary case-patients, 45 had not received AV prophylaxis. The effectiveness of AV prophylaxis in preventing infection was 92%.


Risk Factors for Norovirus Gastroenteritis among Nicaraguan Children.
Norovirus is a leading cause of pediatric gastroenteritis. Understanding norovirus epidemiology is essential for reducing disease burden. We conducted a case-control study to describe the distribution, clinical features, and risk factors of norovirus gastroenteritis among children < 5 years of age in León, Nicaragua. Cases were children testing positive for norovirus and controls were children living in the cases' communities. Study staff interviewed mothers of enrolled cases and controls to obtain detailed exposure information including food, water, and sanitation sources; recent exposures; household characteristics; and handwashing practices. In addition, study staff requested stool samples to be tested for norovirus from select household members. We used descriptive statistics to understand the epidemiologic and clinical features of gastroenteritis episodes. To analyze potential risk factors, we used Firth's penalized logistic regression to estimate crude and adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs). There were 102 children with gastroenteritis, 18 cases of norovirus and 31 controls. Norovirus cases occurred later in the year, corresponding to a delay in the rainy season. Cases were more likely to have a household member with norovirus in their stool as compared with controls [crude OR: 13.3 (95% CI: 2.5, 136.2) and adjusted OR: 11.5 (95% CI: 1.6, 223.2)]. In addition, alcohol-based hand sanitizer use among household members was reported for 10 (32%) of controls and but never for cases. Further research is needed to understand household transmission of norovirus in low- and middle-income countries and the potential impact of hand sanitizer use.


Destination Design msTRAM: For Greater Reconstructive Certainty.
Performing delayed reconstruction to a unilateral breast while simultaneously performing a balancing procedure on the contralateral side can be the most difficult situation to achieve symmetry. We present here a novel approach to free TRAM-based breast reconstruction using reverse planning and subunit principles with simultaneous balancing reduction mastopexy and immediate nipple reconstruction. A retrospective chart review and a BREAST-Q questionnaire of a single surgeon's practice was performed to compare revision rates and patient satisfaction following Destination Design msTRAM reconstruction compared with a historical cohort of patients who received traditional free TRAM reconstruction. The chart review identified 39 patients treated with the traditional unilateral technique from 1997 to 2004 and 88 patients treated with the novel unilateral technique from 2004 to 2017. Traditional technique patients had a breast revision rate of 64.1% and a nipple revision rate of 42.3% after secondary nipple reconstruction. Destination Design patients had a breast revision rate of 44.3% (P = 0.0394) and a nipple revision rate of 37.9% (P = 0.689) after primary nipple reconstruction. The BREAST-Q questionnaire was sent to nine traditional technique patients with 8 responses (89%), and 35 Destination Design patients with 25 responses (71%). Survey results showed that traditional technique and Destination Design patients had an overall breast satisfaction rate of 67.5% and 63.9%, respectively. The Destination Design msTRAM breast reconstruction technique leads to a statistically significant reduction in breast flap revisions, and allows for equally accurate immediate nipple reconstruction compared with traditional methods with no additional complications. Overall patient satisfaction is comparable with both techniques.


Measurement of Tumor Necrosis Factor and Lymphotoxins.
The tumor necrosis factor (TNF) superfamily of cytokines plays critical roles in all aspects of the immune response. TNF and the lymphotoxins (LT), LTα and LTβ, are particularly important as major effector cytokines and mediators or lymphoid organ development. One of the classical methods for the measurement of TNF and LTα activity is by demonstrating their ability to lyse certain target cells. A detailed protocol for the measurement of this activity using a highly sensitive indicator cell line is presented. More recently, ELISA assays have been developed to measure the protein concentration of these cytokines in any type of biologic fluid. © 2017 by John Wiley & Sons, Inc.


Prefrontal cortex oxygenation and neuromuscular responses to exhaustive exercise.
Near-infrared spectroscopy (NIRS) allows non-invasive monitoring of central and peripheral changes in oxygenation during exercise and may provide valuable insight into the factors affecting fatigue. This study aimed to explore the changes in oxygenation of prefrontal cortex and active muscle tissue as limiting factors of incremental exercise performance in trained cyclists. Thirteen trained healthy subjects (mean +/- SE: age 24.9 +/- 1.5 years, body mass 70.1 +/- 1.2 kg, training 6.1 +/- 0.9 h week(-1)) performed a progressive maximal exercise to exhaustion on a cycling ergometer. Prefrontal cortex (Cox) and vastus lateralis muscle (Mox) oxygenation were measured simultaneously by NIRS throughout the exercise. Maximal voluntary isometric knee torques and quadriceps neuromuscular fatigue (M-wave properties and voluntary activation ratio) were evaluated before and after exercise. Maximal power output and oxygen consumption were 380.8 +/- 7.9 W and 75.0 +/- 2.2 ml min(-1) kg(-1), respectively. Mox decreased significantly throughout exercise while Cox increased in the first minutes of exercise but decreased markedly from the workload corresponding to the second ventilatory threshold up to exhaustion (P < 0.05). No significant difference was noted 6 min after maximal exercise in either the voluntary activation ratio or the M-wave properties. These findings are compatible with the notion that supraspinal modulation of motor output precedes exhaustion.


Recurrent acute retrograde intragastric intussusception.
A case of recurrent acute retrograde jejunogastric intussusception is described in a 45-year-old man who five years previously had had an antecolic gastrojejunostomy. Two previous haematemases imply that this complication was recurrent and self reducing an unusual and fortuitous outcome. Awareness of the possibility of acute intussusception following gastroenterostomy or partial gastrectomy is stressed.


HPV infection profile in cervical lesions.
The prevalence of the different genotypes of human papillomavirus (HPV) varies depending on lesion severity and geographic region. To identify multiple HPV infections in low- and high-grade cervical lesions in a group of women from the Mexican Bajío region referred with inconclusive cytology. Pilot study of women referred from primary care units of Guanajuato, Mexico, with cytology suggestive of cervical lesion. Cervical smears were subjected to DNA extraction and HPV genotyping using microarrays. 100 consecutive cases were collected and 90 were analyzed; HPV positivity was observed in 26% of healthy women, and 62% had some degree of cervical lesion. The most common HPV genotypes were 59, 31, 16 and 51. Multiple infections were found in most samples. HPV heterogeneity was identified in the samples of the study population in contrast to worldwide reports; furthermore, multiple infections are common in precursor lesions and decrease in high-grade lesions. These data could have an impact on current HPV vaccination programs.


Draft Genome Sequences of 12 Feline Bartonella henselae Isolates.
Bartonella henselae is the main causative agent of cat scratch disease. In this report, we present the draft genome sequences of 12 strains of Bartonella henselae originating from the United States, Denmark, and France. These strains were isolated from cats and belonged to either 16S rRNA genotype I or 16S rRNA genotype II.


How mechanistic modelling supports decision making for the control of enzootic infectious diseases.
Controlling enzootic diseases, which generate a large cumulative burden and are often unregulated, is needed for sustainable farming, competitive agri-food chains, and veterinary public health. We discuss the benefits and challenges of mechanistic epidemiological modelling for livestock enzootics, with particular emphasis on the need for interdisciplinary approaches. We focus on issues arising when modelling pathogen spread at various scales (from farm to the region) to better assess disease control and propose targeted options. We discuss in particular the inclusion of farmers' strategic decision-making, the integration of within-host scale to refine intervention targeting, and the need to ground models on data.


[Evaluation by MR imaging of the velocity and volume of pre- and postprandial portal blood flow in the presence or absence of liver cirrhosis].
We measured pre- and postprandial changes in the portal flow of normal volunteers and patients with liver cirrhosis using MR imaging and examined how to quantify portal flow to evaluate liver function. Three groups were selected: middle aged normal volunteers (mean age 37.2 yrs., 5 persons), aged normal volunteers (mean age 61.5 yrs., 6 persons), and patients (mean age 67.6 yrs., 7 persons). We used cine-PC and the spin-echo method to measure portal flow velocity (PV) and vertical sectional area (PA), respectively. We repeated measurements of PV and PA in turn for about 60 minutes after a meal. There were no significant differences in PV between the three groups before the meal. Study after the meal also indicated no significant difference between the two normal groups. In the normal group, PV and portal flow volume (Pvol.) increased by about 77% and 127%, respectively. In the cirrhotic liver group, PV and Pvol. increased by about 14% and 32%, respectively. A significant difference was seen between the normal and patient groups after the meal. We, therefore considered that the changing rate of Pvol. might be a sensitive parameter for evaluating liver function, including reserve.


Integrating Advance Care Planning Into Practice.
Advanced respiratory diseases progress over time and often lead to death. As the condition worsens, patients may lose medical decision-making ability. Advance care planning (ACP) is a process in which patients receive information about their diagnosis and prognosis; discuss values, goals, and fears; articulate preferences about life-sustaining treatments and end-of-life care; and appoint a surrogate medical decision maker. This process may result in written documentation of patient preferences or the appointment of a health-care power of attorney (HCPOA). ACP discussions have multiple benefits for patients and their surrogate decision makers, including ensuring that the care provided is aligned with the patient's goals and preferences and decreasing stress, anxiety, and burden in surrogates. Time and provider comfort are often cited barriers to ACP, so it may be necessary for clinicians to gain experience in conversations and identify the patients most likely to benefit from ACP discussions. Two new Current Procedural Terminology (CPT) codes, 99497 and 99498, have been recognized by the Centers for Medicare and Medicaid Services (CMS) as of January 1, 2016 and are intended to incentivize clinicians to engage in ACP discussions with their patients earlier and with more frequency. This manuscript reviews the benefits and barriers to ACP in patients with advanced respiratory disease and provides guidance on the use of the new CPT codes for reimbursement of these conversations.


Many family physicians will not manually update PDA software: an observational study.
In a prospective study to explore connections between clinical information delivery and information retrieval, 41 Canadian family physicians searched an electronic knowledge resource (EKR) as needed for practice. Research software, called the Information Assessment Method (IAM), prompted family physicians to report on the situational relevance, perceived cognitive impact and application of their retrieved information hits. Both the IAM and the EKR needed periodic updating to properly address our research questions. To determine the frequency of software updating when manual or semi-automatic approaches are used by family physicians. Each family physician received a handheld computer (PDA) that ran the Windows Mobile 6 operating system. For technical reasons, both the IAM and the EKR were accessed offline on PDA. To update the EKR and the IAM, family physicians were asked to synchronize their PDA to their PC. Updating the IAM was a manual process, whereas updating the EKR was semi-automatic. We found: (1) about 25% of family physicians never or rarely updated PDA software on their own, (2) a large number of software updates were never installed and (3) the semi-automatic method was associated with a small increase in the proportion of installed software updates (58.9% versus 48.6% for the manual method). When a wireless internet connection is not used to update PDA software, sociotechnical issues complicate mobile data collection and data transfer.


Timing of death and myocardial infarction in patients with non-ST elevation acute coronary syndromes: insights from randomized clinical trials.
Adverse events occur following non-ST elevation acute coronary syndromes (NSTE ACS). However, the timing of these events in relation to index event is less clear. Accordingly, we evaluated 26,466 NSTE ACS patients from the Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes (GUSTO-IIb), Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT), and Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network (PARAGON) A and B trials to ascertain the timing of adverse events. Outcomes of interest were death, myocardial infarction (MI), and death or MI at 180 days. Logistic regression modeling for death was used to categorize patients into low-, medium-, and high-risk groups. At 6 months, 6.2% of patients died, 12.1% had MI, and 15.7% suffered death or MI. From 15% to 40% of these events occurred beyond 30 days. At 6 months, 3%, 4%, and 13% of patients died in low-, medium-, and high-risk groups, respectively. However, the proportion of patients dying beyond 30 days was similar in the three groups (44%, 43%, and 41% of death, respectively). Similarly, whereas death or MI increased with higher risk (11%, 14%, and 23%, respectively), the proportion of patients with this event beyond 30 days did not differ in the three strata (22%, 20%, and 25%, respectively). Our study provides important insights into the timing of adverse events and suggests that the substantial proportion of patients suffer subsequent adverse events after their index NSTE ACS. Thus, these data call for continuous surveillance for these events and efforts beyond the acute phase at increasing adherence to evidence-based therapies to improve the outcomes of these patients.


[A case of vesical paraganglioma with intrapelvic multiplicity].
A 35-year-old woman, who had a past history of hypertension due to paraganglioma of the urinary bladder and in the pelvis, was referred to us 12 years after the initial diagnosis of paraganglioma. Before coming to us and during the follow-up after enucleation of myoma uteri, she was again diagnosed as having a bladder tumor by a gynecologist. Cystoscopy revealed a non-papillary broad-based tumor, measuring 2 cm in diameter, on the trigone of the urinary bladder. Magnetic resonance imaging also showed two solid tumors, each measuring 2 cm in diameter, on the bilateral peri-vesical sides in the pelvis. Endocrinologic examination disclosed increased levels of serum and urinary catecholamines. Histopathologic examination revealed that the bladder tumor specimen obtained by transurethral resection was paraganglioma. She underwent partial cystectomy and resection of these intrapelvic tumors via a retroperitoneal approach. These tumors were histopathologically diagnosed as multiple paragangliomas. She has been followed up for 10 months after operation without any evidence of recurrence. Herein, we report this rare case of vesical paraganglioma and present a brief review of the relevant literature.


Occurrence of occult CSF leaks during standard FESS procedures.
To determine the incidence of occult cerebrospinal fluid leaks (CSF) after functional endoscopic sinus surgery (FESS) and to evaluate the diagnostic performance of beta2-transferrin in blood-contaminated conditions. Prospective cohort study. An analysis of 57 intraoperative samples using hydrogel 6 beta2-transferrin assay after FESS was undertaken. In case of CSF positive samples and continuing rhinorrhea, reanalysis after more than 1 year was conducted. In-vivo analysis of a primary spontaneous CSF leak sample took place to verify difficulties in detecting beta2-transferrin in blood-contaminated settings. Own titrations were performed to evaluate detection limits of CSF by beta2-transferrin and beta-trace protein assays in these settings. An incidence of 13% for occult CSF leaks after FESS was found. In blood-contaminated conditions, routine beta2-transferrin assays showed low sensitivity. In over 1 year follow-up, all samples were negative for CSF and none of them developed clinical relevant CSF leaks or meningitis. Occult and clinically irrelevant CSF leaks do occur in a significant proportion of patients during and shortly after FESS. Intra- and postoperatively, routine beta2-transferrin assays show low sensitivity. They should not be used in these settings. The clinical course of patients with occult CSF leaks indicated possibility of an uneventful follow-up.


Achieving a shared vision for girls' health in a low-income community.
In response to a lack of information related to girls' health in a low-income community, an initiative was developed to create a community-wide vision for girls' health. A forum was conducted following a photovoice project to generate sustainable action steps. Forty-four participants attended the forum. Key action steps included decreasing barriers to participation in girls' programs, offering leadership roles and interpersonal communication skills for girls in the community, and engaging girls in community organizations. Integral to the forum's success were the initial photos, which provided a bridge from understanding the issues of girls' health to the development of the action steps.


Lymphangiogenesis and colorectal cancer.
Lymphatic metastasis is an important event in the progress of metastasis in colorectal cancer (CRC). The purpose of this article is to assess the role of lymphangiogenesis on CRC. In peritumoral areas of CRC, the lymphatic microvessel density (LMVD) is higher than those in normal colorectal tissues. Morever, the high LMVD is correlated with DFS and local recurrence in CRC. The VEGF-C/VEGF-D/VEGFR-3 pathway, sonic hedgehog (Shh) signaling pathway and extracellular matrix (ECM) are involved in the regulation of lymphangiogenesis in CRC. Inhibition of the VEGF-C/VEGF-D/VEGFR-3 pathway by specific antibodies has been reported to efficiently inhibit experimental tumor lymphangiogenesis and metastasis in animal experiments. Although lymphangiogenesis has been reported to play an important role in the occurrence of colon cancer and to be associated with prognosis, it remains unclear whether it is a valid therapeutic target molecule. Further study of the potential of targeting this process for anti-lymphatic therapies is worthwhile.


The Effects of Crocin on Bone and Cartilage Diseases.
Crocin, the main biologically active carotenoid of saffron, generally is derived from the dried trifid stigma of Crocus sativus L. Many studies have demonstrated that crocin has several therapeutic effects on biological systems through its anti-oxidant and anti-inflammatory properties. The wide range of crocin activities is believed to be because of its ability to anchor to many proteins, triggering some cellular pathways responsible for cell proliferation and differentiation. It also has therapeutic potentials in arthritis, osteoarthritis, rheumatoid arthritis, and articular pain probably due to its anti-inflammatory properties. Anti-apoptotic effects, as well as osteoclast inhibition effects of crocin, have suggested it as a natural substance to treat osteoporosis and degenerative disease of bone and cartilage. Different mechanisms underlying crocin effects on bone and cartilage repair have been investigated, but remain to be fully elucidated. The present review aims to undertake current knowledge on the effects of crocin on bone and cartilage degenerative diseases with an emphasis on its proliferative and differentiative properties in mesenchymal stem cells.


The Impact of Pollution Prevention on Toxic Environmental Releases from U.S. Manufacturing Facilities.
Between 1991 and 2012, the facilities that reported to the U.S. Environmental Protection Agency's Toxic Release Inventory (TRI) Program conducted 370,000 source reduction projects. We use this data set to conduct the first quasi-experimental retrospective evaluation of how implementing a source reduction (pollution prevention) project affects the quantity of toxic chemicals released to the environment by an average industrial facility. We use a differences-in-differences methodology, which measures how implementing a source reduction project affects a facility's releases of targeted chemicals, relative to releases of (a) other untargeted chemicals from the same facility, or (b) the same chemical from other facilities in the same industry. We find that the average source reduction project causes a 9-16% decrease in releases of targeted chemicals in the year of implementation. Source reduction techniques vary in effectiveness: for example, raw material modification causes a large decrease in releases, while inventory control has no detectable effect. Our analysis suggests that in aggregate, the source reduction projects carried out in the U.S. since 1991 have prevented between 5 and 14 billion pounds of toxic releases.


Image distortion in MRI-based polymer gel dosimetry of gamma knife stereotactic radiosurgery systems.
We have studied effects of MR (magnetic resonance) image distortion on polymer gel dosimetry of Gamma Knife stereotactic radiosurgery systems. MR images of BANG polymer gel phantoms were acquired by using a Hahn spin-echo sequence and a fast 3D imaging GRASS sequence. Image artifacts were studied by varying the directions of frequency encoding and the receiver bandwidth. The phantoms were also CT (computed tomography) scanned. The studies showed that the measured dose distributions are shifted by 1.8+/-0.5 mm (2 pixels) in the frequency encoding direction. The magnitude of the shift is inversely proportional to the receiver bandwidth in agreement with theory. Comparison of MRI with CT showed the same image shift. We concluded that the discrepancy is caused by MR image distortion due to a difference in susceptibility effects between the phantom and the fiducial markers of the Leksell localization box.


Impact of an Atrial Fibrillation Decision Support Tool on thromboprophylaxis for atrial fibrillation.
Appropriate thromboprophylaxis for patients with atrial fibrillation (AF) remains a national challenge. We hypothesized that provision of decision support in the form of an Atrial Fibrillation Decision Support Tool (AFDST) would improve thromboprophylaxis for AF patients. We conducted a cluster randomized trial involving 15 primary care practices and 1,493 adults with nonvalvular AF in an integrated health care system between April 2014 and February 2015. Physicians in the intervention group received patient-level treatment recommendations made by the AFDST. Our primary outcome was the proportion of patients with antithrombotic therapy that was discordant from AFDST recommendation. Treatment was discordant in 42% of 801 patients in the intervention group. Physicians reviewed reports for 240 patients. Among these patients, thromboprophylaxis was discordant in 63%, decreasing to 59% 1 year later (P = .02). In nonstratified analyses, changes in discordant care were not significantly different between the intervention group and control groups. In multivariate regression models, assignment to the intervention group resulted in a nonsignificant trend toward decreased discordance (P = .29), and being a patient of a resident physician (P = .02) and a higher HAS-BLED score predicted decreased discordance (P = .03), whereas female gender (P = .01) and a higher CHADSVASc score (P = .10) predicted increased discordance. Among patients whose physicians reviewed recommendations of the decision support tool discordant therapy decreased significantly over 1 year. However, in nonstratified analyses, the intervention did not result in significant improvements in discordant antithrombotic therapy.


Selective Synthesis of (+)-Dysoline.
Dysoline, a novel chromone alkaloid isolated from Dysoxylum binectariferum, was reported to have selective cytotoxicity for HT1080 fibrosarcoma cells (IC50 of 0.21 μM). Given the scarcity of natural material, a concise synthesis of (+)-dysoline was developed, allowing for further biological evaluation. An enantioselective nucleophile-catalyzed aldol lactonization formed the piperidine ring with control of relative and absolute stereochemistry. Construction of the C6-chromone core with complete regioselectivity was achieved using a Danheiser benzannulation.


Focus on fatigue amongst young adults with spastic cerebral palsy.
This study aimed to assess fatigue amongst young adults with spastic cerebral palsy (CP), to determine subgroups at risk for fatigue and to explore the relationship between fatigue and cardiopulmonary fitness and daily physical activity level. Young adults with spastic CP, Gross Motor Function Classification System (GMFCS) levels I to III, aged 16 to 24 years. Fatigue (Fatigue Severity Scale) and self-reported daily physical activity (Physical Activity Scale for Individuals with Physical Disabilities) were assessed for 56 participants using questionnaires. Daily physical activity was objectively measured using accelerometry (Vitamove system) over 72 hours. Progressive maximal aerobic cycling was used to measure cardiopulmonary fitness. The mean Fatigue Severity Scale (FSS) score was 3.7 (SD 1.4). Forty percent of participants were fatigued, including 12.5% who were severely fatigued. Participants with bilateral CP (FSS = 4.2 (SD 1.4)) were more fatigued compared to those with unilateral CP (FSS = 3.1 (SD 1.3)) (p < 0.01). Levels of cardiopulmonary fitness (2.4 L/min (SD 0.8)) and daily physical activity (8.5% (SD 3.0)) were not significantly related to fatigue (respectively p = 0.10 and p = 0.55), although for cardiopulmonary fitness a trend was found. Fatigue is already present at a relatively young age amongst adults with CP, and CP subtype is a determinant of fatigue. We did not find significant evidence for a cross-sectional relation of fatigue with cardiopulmonary fitness or daily physical activity. Nederland's trial register: NTR1785.


Salvage cryotherapy for recurrent prostate cancer after radiotherapy: variables affecting patient outcome.
To determine the long-term disease-specific survival (DSS) and disease-free survival (DFS) rates after salvage cryotherapy for locally recurrent adenocarcinoma of the prostate and to identify pretreatment factors that have an impact on DSS and DFS. Between July 1992 and January 1995, 131 patients who had received definitive radiation therapy (XRT) underwent salvage cryotherapy for locally recurrent adenocarcinoma of the prostate. Cryotherapy failure was defined as an increasing postcryotherapy prostate-specific antigen (PSA) level of > or = 2 ng/mL above the postcryotherapy nadir, a positive prostate biopsy, or radiographic evidence of metastatic disease. Clinical variables were studied to determine whether there was an association with the DSS and DFS. The median follow-up was 4.8 years. The 5-year DSS rates were 87% for patients with a precryotherapy Gleason score < or = 8 and 63% for those with Gleason scores of 9 and 10 (P =.012). The 5-year DFS rates were 57% for patients with a precryotherapy PSA level of < or = 10 ng/mL and 23% for those with a PSA level greater than 10 ng/mL (P =.0004). The 5-year DSS rates for patients with a pre-XRT clinical stage of T1 to T2 and those with a clinical stage of T3 to T4 were 94% and 72%, respectively (P =.0041). The 5-year DFS rates for these groups were 90% and 69%, respectively (P =.0057). Androgen-independent local recurrences, Gleason score, and pre-XRT clinical stage were important factors that had an impact on DSS and DFS. The subset of patients cured by salvage cryotherapy seems to be small, and patient selection is important.


The thyroid hormone receptor variant alpha2 is a weak antagonist because it is deficient in interactions with nuclear receptor corepressors.
The thyroid hormone receptor splice variant, alpha2, is unable to bind thyroid hormone (T3) and has been proposed to function as an endogenous inhibitor of T3 action. In this report, we examined further the DNA sequence requirements for alpha2 binding to thyroid hormone response elements (TREs) in an attempt to identify response elements that mediate potent inhibition by alpha2. Heterodimers of alpha2 and retinoid X receptor were found to bind to a subset of TREs (DR4, direct repeats spaced by 4 bp) in which selected flanking and spacer sequences enhanced interactions with the AGGTCA core binding sequence. Despite the optimization of the TRE-binding sites, alpha2 remained a weak dominant negative inhibitor of TRE-driven transcription. A promoter interference assay was also developed for testing inhibition by alpha2. In these studies, alpha2 blocked gene transcription, but it required cotransfected retinoid X receptor, and it was not as potent as unliganded thyroid hormone receptors. These results led to the hypothesis that alpha2 might be deficient in interactions with nuclear receptor corepressors. Consistent with this view, alpha2 did not silence basal transcription in its native form or when linked to Gal4. Alpha2 also failed to interact with corepressors (NCoR and SMRT) in both gel shift assays and mammalian two-hybrid assays. We conclude that alpha2 is a weak antagonist of thyroid hormone action because it binds weakly to a limited repertoire of response elements, and it does not interact with corepressors. Thus, alpha2 may be able to compete with thyroid hormone receptors for binding to a limited group of target sites, but it is not able to actively inhibit transcription.


Oxcarbazepine causes neurocyte apoptosis and developing brain damage by triggering Bax/Bcl-2 signaling pathway mediated caspase 3 activation in neonatal rats.
Anti-epileptic drugs (AEDs) are the main methods for treatment of neonatal seizures; however, a few AEDs may cause developing brain damage of neonate. This study aims to investigate effects of oxcarbazepine (OXC) on developing brain damage of neonatal rats. Both of neonatal and adult rats were divided into 6 groups, including Control, OXC 187.5 mg/kg, OXC 281.25 mg/kg, OXC 375 mg/kg group, LEV and PHT group. Body weight and brain weight were evaluated. Hematoxylin and eosin (HE) and Nissl staining were used to observe neurocyte morphology and Nissl bodies, respectively. Apoptosis was examined using TUNEL assay, and caspase 8 activity was evaluated using spectrophotometer method. Cytochrome C-release was evaluated using flow cytometry. Western blot was used to examine Bax and Bcl-2 expression. OXC 375 mg/kg treatment significantly decreased brain weight compared to Control group in neonatal rats (P5 rats) (p<0.05). OXC administration causes histological changes of neurocytes. OXC 281.25 mg/kg or more concentration significantly decreased neurocytes counts and increased TUNEL-staining positive neurocytes compared to Control group (p<0.05). OXC 281.25 mg/kg and OXC 375 mg/kg significantly increased caspase 3 activity compared to Control group in P5 rats (p<0.05). OXC 281.25 mg/kg and OXC 375 mg/kg significantly increased Bax, Bax/Bcl-2 ratio and cytochrome C release in frontal lobes compared to Control group in P5 rats (p<0.05). Oxcarbazepine at a concentration of 281.25 mg/kg or more causes neurocyte apoptosis and developing brain damage by triggering Bax/Bcl-2 signaling pathway mediated caspase 3 activation in neonatal rats.


Effect of electron beam irradiation on biomechanical properties of patellar tendon allografts in anterior cruciate ligament reconstruction.
Sterilization of anterior cruciate ligament (ACL) allografts is an important prerequisite to prevent disease transmission. However, mechanical tissue properties are compromised by most current sterilization procedures, so that uncompromised sterilization of allografts is difficult to achieve. Hypothesis/ The aim of this study was to evaluate the effect of the novel electron beam sterilization procedure on the biomechanical properties of human patellar tendon allografts at various irradiation dosages. Electron beam sterilization may be an appropriate alternative to gamma sterilization. Controlled laboratory study. Thirty-two human 10-mm wide bone-patellar tendon-bone grafts were randomized into 4 groups of sterilization with 15, 25, or 34 kGy of electron beam irradiation, respectively. The grafts' biomechanical properties were evaluated at time zero. Unsterilized grafts functioned as controls. Biomechanical properties were analyzed during cyclic and load-to-failure testing. Strain and cyclic elongation response showed no significant differences between the groups. Electron beam irradiation had no significant effect on stiffness and failure load with the exception of 34 kGy, which resulted in a significant decrease in failure load (1300.6 +/- 229.2 N) compared with unsterilized grafts (1630.5 +/- 331.1 N). This study showed that electron beam might be an appropriate alternative in sterilization of patellar tendon allografts with minimal effect on mechanical properties of tendon grafts in vitro. Future studies will have to evaluate the effect of the process on the biological properties of allografts in vitro and in vivo. Terminal sterilization of patellar tendon allografts with electron beam irradiation can ensure higher safety of transplanted grafts and hence improve patient safety and acceptance.


Utilisation of antibiotic therapy in community practice.
The aim of the study was to identify outpatient antibiotic consumption between Jan 2000 and Dec 2005 through analysis of the HSE-Primary Care Reimbursement Services (PCRS) database as part of the Surveillance of Antimicrobial Resistance in Ireland (SARI) project. Total antibiotic consumption on the PCRS scheme between January 2000 and December 2005 expressed in Defined Daily Dose per 1000 PCRS inhabitants per day increased by 26%. The penicillin group represents the highest consumption accounting for approximately 50% of the total outpatient antibiotic use. Total DIDs for this group increased by 25% between 2000 and 2005. Co-amoxiclav and amoxicillin account for 80% of the total consumption of this group of anti-infectives. With the exception of aminoglycosides and sulfonamides which demonstrated a decrease in DID consumption of 47% and 8% respectively, all other groups of anti-infectives had an increase in DID consumption of greater than 25% during the study period. Antibiotic prescribing data is a valuable tool for assessing public health strategies aiming to optimise antibiotic prescribing.


Nonlinear bending models for beams and plates.
A new nonlinear model for large deflections of a beam is proposed. It comprises the Euler-Bernoulli boundary value problem for the deflection and a nonlinear integral condition. When bending does not alter the beam length, this condition guarantees that the deflected beam has the original length and fixes the horizontal displacement of the free end. The numerical results are in good agreement with the ones provided by the elastica model. Dynamic and two-dimensional generalizations of this nonlinear one-dimensional static model are also discussed. The model problem for an inextensible rectangular Kirchhoff plate, when one side is clamped, the opposite one is subjected to a shear force, and the others are free of moments and forces, is reduced to a singular integral equation with two fixed singularities. The singularities of the unknown function are examined, and a series-form solution is derived by the collocation method in terms of the associated Jacobi polynomials. The procedure requires solving an infinite system of linear algebraic equations for the expansion coefficients subject to the inextensibility condition.


The effect of diaphragmatic peritoneal lymphatics on peritoneal adhesions: an experimental study.
In this study, we examined the effect of diaphragmatic peritoneal lymphatic function on the formation of peritoneal adhesions. A two phased design was used in fifty-two Wistar albino female rats. In the first phase (n = 12), the effects of diaphragmatic peritoneum damage model on the cecum and the terminal ileum were evaluated. In the second phase, the rats (n = 40) were divided into two equal groups. The adhesion model was created only in the cecum and the terminal ileum in the first group, whereas the diaphragmatic peritoneal damage model was created in the second group together with the same adhesion model. The rats were sacrificed on day 10 postoperatively and the adhesions formed were graded. In the first group, adhesions were formed at grade 1 in 5 rats (25%), grade 2 in 11 rats (55%) and grade 3 in 4 rats (20%), whereas adhesions were formed at grade 1 in 2 rats (10%), grade 2 in 8 rats (40%) and grade 3 in 10 rats (50%) in the second group (X2: 21.65, p < 0.0001). Diaphragmatic peritoneal lymphatic function reduced the number of adhesions and severity of the adhesions which occurred among intraabdominal organs after laparotomy. These findings suggest that special care should be undertaken to avoid damaging the diaphragmatic peritoneum during abdominal surgery so as to reduce the incidence of peritoneal adhesions.


The Mechanical Interplay Between Differentiating Mesenchymal Stem Cells and Gelatin-Based Substrates Measured by Atomic Force Microscopy.
Traditional methods to assess hMSCs differentiation typically require long-term culture until cells show marked expression of histological markers such as lipid accumulation inside the cytoplasm or mineral deposition onto the surrounding matrix. In parallel, stem cell differentiation has been shown to involve the reorganization of the cell's cytoskeleton shortly after differentiation induced by soluble factors. Given the cytoskeleton's role in determining the mechanical properties of adherent cells, the mechanical characterization of stem cells could thus be a potential tool to assess cellular commitment at much earlier time points. In this study, we measured the mechanical properties of hMSCs cultured on soft gelatin-based hydrogels at multiple time points after differentiation induction toward adipogenic or osteogenic lineages. Our results show that the mechanical properties of cells (stiffness and viscosity) and the organization of the actin cytoskeleton are highly correlated with lineage commitment. Most importantly, we also found that the mechanical properties and the topography of the gelatin substrate in the vicinity of the cells are also altered as differentiation progresses toward the osteogenic lineage, but not on the adipogenic case. Together, these results confirm the biophysical changes associated with stem cell differentiation and suggest a mechanical interplay between the differentiating stem cells and their surrounding extracellular matrix.


Venlafaxine: a novel antidepressant that has a dual mechanism of action.
Major depressive disorder (MDD) is a common affective disorder that is associated with a range of psychiatric disturbances. The pathophysiology of MDD is commonly believed to involve the reduced availability of the monoamines, serotonin (5-HT) and norepinephrine (NE), the enhancement of which is also believed to mediate, at least in part, the therapeutic effects of antidepressants. The first-generation antidepressants, the tricyclic antidepressants (TCAs), provide considerable efficacy but have several limitations, including (1) delayed onset of action, (2) intolerable or distressing side effects, (3) low therapeutic index, and (4) a significant proportion of nonresponders. The second-generation antidepressants, the selective-serotonin-reuptake inhibitors (SSRIs), mitigate some of the side effects associated with the TCAs by selectively inhibiting the reuptake of 5-HT. Venlafaxine is a new antidepressant that blocks reuptake of both 5-HT and NE. It, like the SSRIs, has a relatively benign side-effect profile. In addition, it may exert a rapid onset of action, and it appears to be particularly effective in moderate-to-severe depression and in patients who have treatment-refractory depression.


Study of anthocyanic profiles of twenty-one hybrid grape varieties by liquid chromatography and precursor-ion mass spectrometry.
The anthocyanins of 21 hybrid red varieties produced by crossing V. vinifera, V. riparia, V. labrusca, V. lincecumii and V. rupestris species, the profiles for which have not yet been reported, were studied. Profiles were determined by LC/DAD, and identification of single anthocyanins was confirmed by LC/MS precursor-ion analysis. Anthocyanidin precursors (pelargonidin at m/z 271, dephinidin at m/z 303, cyanidin at m/z 287, petunidin at m/z 317, peonidin at m/z 301, and malvidin at m/z 331) and precursors of monoglucoside compounds allowed 24 different compounds to be identified. Analysis of precursor ions of monoglucoside anthocyanins at low capillary voltage revealed the signals of diglucosides only, providing a very selective method for analysis of diglucoside anthocyanins in grape. According to anthocyanin profile, the samples were subdivided into two groups: one characterized by the substantial presence of diglucoside compounds (particularly Seyve Villard 23-399 and Seyve Villard 23-369) and one by the scarce presence or practical absence of diglucosides (Seibel 10878, Burdin 4077, and Galibert 238-35). Particularly interesting for producing anthocyanin for the natural colorant industry were the varieties Siebel 8357, Bacò 30-12 and Terzi 100-31.


Currents and Prospects of the Clinical Applications of the Third-generation Dual-source CT.
Compared with the conventional dual-source CT,the third-generation dual-source CT has many technical advantages in terms of tube function,iterative reconstruction,and dual-energy scanning mode. Many studies have explored the "double low" applications of this technique,and the future research will be focused on disease diagnosis,removal of artifacts,organ perfusion,and substance separation.


[Must the concept of intrinsic asthma be supported?].
Intrinsic asthma, defined as asthma which is not from allergy to pneumo-allergens, of cause unknown, may show several etiologies. Allergics, remembering that there in some subjects there may be small amounts of IgE on the mastocytes, with specific RAST IgE negative, skin tests only weakly positive, but with a positive provocation test to pneumo-allergens. Food allergy, isolated and associated, may also contribute a not-negligible cause. Non-allergics, responding to the frequent triggering factors: Gastro-oesophageal reflux; Neuro-endocrine origin; Infections; Physical origin (exercise). In our study, we quote two types of extremely severe asthma, linked to intolerance to aspirin and metabisulfites with others that are associated.


[The development of local nonexcitability in sinus node cells and other cells with diastolic depolarization in the right atrium of the rabbit under the action of acetylcholine].
The sinus node is heterogeneous structure. In the intact sinus node acetylcholine induced shift of pacemaker from the center of sinus node suggesting higher sensitivity of typical pacemaker cells to acetylcholine. The aim of this study was to compare the acetylcholine (10(-5), 10(-4) M) action on different cell types in the intercaval region as well as in the sinus node. The rabbit right atrium, with the sinus node region intact, was pinned in a tissue bath. One or two microelectrodes were impaled in the sinus node and atrial electrogram was obtained simultaneously. During superfusion with acetylcholine though the preparations retained regular rhythm some of the cells with diastolic depolarization became inexcitable, their amplitude fell below 30% of the control value while others did not. In pacemaker cells (upstroke velocity < 5 V/s; smooth transition from diastolic depolarization into upstroke) occurrence of inexcitability was the highest: 36 of 40 cells (90%). With increasing upstroke velocity, the occurrence of inexcitability decreased. Effects of acetylcholine were completely reversible and were blocked by pretreatment with atropine 10(-7) M. It may be suggested that particular sensitivity of typical pacemaker cells to acetylcholine could arise from two facts: 1. In typical pacemaker cells calcium current plays the main role in action potential upstroke; 2. The calcium current in the sinus node cells is particular sensitive to acetylcholine.


The relevance of ESBL producing isolates in patients surgically treated for acute appendicitis.
In India, there is a high prevalence of ESBL producing organisms among intraabdominal isolates and in stool flora of 'normal' individuals. Hence, it may be presumed that unless antimicrobial therapy effective for ESBL flora is used perioperatively for abdominal surgery, the outcome will be adverse. We selected patients surgically treated for appendicitis as a model to explore the relevance of ESBL producing isolates in this retrospective observational study. To assess the impact of ESBL producing isolates in patients surgically treated for acute appendicitis and to determine whether the perioperative antibiotic use needs to be changed in view of the high ESBL prevalence. Chart review of 221 consecutive patients who had undergone appendicectomy between January 2004 and December 2009. 55 of 221 patients had cultures of relevant specimens done based on the discretion of the treating surgeon. 40 yielded 1 or more organisms. 19 showed ESBL producing Enterobacteriaceae (ESBL+) and 21 showed non ESBL producing Enterobacteriaceae (ESBL-). 118 of 221 patients had presented without any complications and had a good outcome after surgery. The other 33 of 221 patients had complications like perforation or an abscess at presentation. Out of these, 16 patients received inappropriate therapy and 17 received appropriate therapy. The patients with appropriate therapy had good outcome. Among the 16 patients with inappropriate therapy 15 were ESBL+and 1 was ESBL-. Out of the 15 ESBL+isolates, 9 developed an initial postoperative complication like postoperative fever or wound infection. The cultures of the relevant specimen were done in all these 9 patients, all of which were positive. Therapy was changed in 7 of these 9 patients to pathogen directed therapy like amikacin, chloramphenicol and levofloxacin. Meropenem was used in only one case. All these 7 patients as well as the 2 patients whose treatment was not changed made a complete recovery. For patients surgically treated for acute appendicitis, a change of perioperative antibiotics to those effective for ESBL+organisms is not needed at present only on the basis of ESBL prevalence rates. Routine cultures may not be necessary. Cultures are needed if there is a complication such as an abscess or perforation at presentation or an initial post operative complication. A change to pathogen directed therapy, including even to older or non beta-lactam antimicrobials may be needed in these cases. Our results support continuing the use of older antimicrobials rather than changing to carbapenems and beta-lactamase-beta-lactamase inhibitor combination in low risk surgically treated patients. This may prevent generation of further resistance without compromising outcomes.


Renal clearance of cobalt in relation to the use of metal-on-metal bearings in hip arthroplasty.
A concern regarding the use of metal-on-metal bearings in hip arthroplasty has been that the high levels of metal ions that are released overwhelm the renal threshold for metal excretion, leading to systemic buildup of metals. The purpose of this investigation was to determine if the physiological renal capacity for cobalt clearance and cobalt concentrating efficiency is overwhelmed by the elevation in metal ion levels seen in patients with metal-on-metal-bearing hip devices. Concurrent specimens of urine and plasma were obtained from a group of 461 patients (346 men and 115 women) at various intervals after either a unilateral (296) or a bilateral (130) metal-on-metal hip arthroplasty or preoperatively (thirty-five patients; the control specimens). Metal ion analyses were performed with high-resolution inductively coupled mass spectrometry. Renal efficiency was measured as the ratio of urine cobalt concentration to plasma cobalt concentration. Cobalt clearance was calculated by dividing the urine cobalt output in twenty-four hours by the plasma cobalt concentration. Dividing the quotient by 1440 adjusts it to clearance per minute. The median renal efficiency was found to be 0.9 in the analysis of the preoperative specimens, indicating that there was renal conservation of cobalt. In patients with metal-on-metal bearings, the median renal efficiency was 3.2, indicating that, as a result of cobalt excretion, the cobalt concentration in urine was threefold higher than the concentration in plasma. Linear regression analysis showed that renal efficiency progressively increased at a rate of 9% for every microg/24 hr increase in cobalt release. Cobalt clearance showed a similar trend, increasing from 1.3 mL/min in the preoperative group to 3.7 mL/min in the follow-up group. In the follow-up group, renal cobalt clearance progressively increased from 1.9 to 7.1 mL/min with increasing daily cobalt output, which indicates that with increasing in vivo metal ion release there was a progressive increase in the rate at which the kidneys cleared the plasma of cobalt. In subjects with no prosthetic device, the kidneys tend to conserve cobalt in the body. We found that, in patients with a metal-on-metal hip prosthesis, there is a progressive increase in cobalt clearance with increasing in vivo wear at the levels of cobalt release expected in patients with an array of metal-on-metal-bearing total joint arthroplasties. We found no threshold beyond which renal capacity to excrete these ions is overwhelmed.


A combined treatment for patients with dry eye and associated laryngopharyngeal reflux: a real-life approach.
To evaluate the efficacy and tolerability of administering a combined therapy in patients with dry eye syndrome (DES) and associated laryngopharyngeal reflux (LPR). The study was retrospective, open, observational, and conducted in a real-life setting. Patients had pathological symptom assessment in dry eye (SANDE) and reflux symptom index (RSI) at baseline. Patients were re-assessed after 1mo and at the end of treatment. The treatment consisted of a three-month course based on the combined therapy: Gastroftal eye drops, one drop three times a day, and Gastroftal tablets, two tablets after lunch and two tablets after dinner. Tear break-up-time (TBUT) test, Schirmer test, RSI, and SANDE questionnaire were evaluated. The study included 253 patients. The mean age was 58±11.19y. TBUT test score and Schirmer's test significantly increased (both P<0.001) after 1mo and at the end of treatment. The RSI score and SANDE scores significantly decreased (both P<0.001) after 1mo and at the end of treatment. The current, retrospective, and open study shows that combined therapy using Gastroftal eye drops and tablets could represent a valuable option in managing patients with DES associated with LPR.


Determination of traces of fipronil and its metabolites in pollen by liquid chromatography with electrospray ionization-tandem mass spectrometry.
Fipronil is a pesticide suspected of having harmful effects on honey bees at microgram per kilogram levels. Considering the lack of methodology, it thus appeared to be necessary to develop a method for the determination of the lowest amounts of fipronil and its metabolites in pollen. This paper describes a new analytical method with a limit of quantification (LOQ) of 0.1 microg/kg for a representative sample weight of 5 g. In the case of a field study, this tool was used for checking the possible existence of fipronil and/or metabolites in pollen samples, but none of them contained residues higher than the LOQ. This three-step rapid method uses liquid-solid solvent extraction with mechanical grinding, followed by liquid-liquid partitioning and Florisil solid-phase extraction for the two cleanup steps. The quantification is made by liquid chromatography with electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Indeed, combined with an adequate sample treatment, this technique offers good sensitivity and selectivity in such a complex matrix. The method has given good recoveries of 74-104% with relative standard deviations of 5.6-18.2%.


Nanotechnology applications in medicine and dentistry.
Nanotechnology, or nanoscience, refers to the research and development of an applied science at the atomic, molecular, or macromolecular levels (i.e. molecular engineering, manufacturing). The prefix "nano" is defined as a unit of measurement in which the characteristic dimension is one billionth of a unit. Although the nanoscale is small in size, its potential is vast. As nanotechnology expands in other fields, clinicians, scientists, and manufacturers are working to discover the uses and advances in biomedical sciences. Applications of nanotechnology in medical and dental fields have only approached the horizon with opportunities and possibilities for the future that can only be limited by our imagination. This paper provides an early glimpse of nanotechnology applications in medicine and dentistry to illustrate their potentially far-reaching impacts on clinical practice. It also narrates the safety issues concerning nanotechnology applications.


The biology and clinical relevance of the PTEN tumor suppressor pathway.
Genetic alterations targeting the PTEN tumor suppressor gene are among the most frequently noted somatic mutations in human cancers. Such lesions have been noted in cancers of the prostate and endometrium and in glioblastoma multiforme, among many others. Moreover, germline mutation of PTEN leads to the development of the related hereditary cancer predisposition syndromes, Cowden disease, and Bannayan-Zonana syndrome, wherein breast and thyroid cancer incidence is elevated. The protein product, PTEN, is a lipid phosphatase, the enzymatic activity of which primarily serves to remove phosphate groups from key intracellular phosphoinositide signaling molecules. This activity normally serves to restrict growth and survival signals by limiting activity of the phosphoinositide-3 kinase (PI3K) pathway. Multiple lines of evidence support the notion that this function is critical to the ability of PTEN to maintain cell homeostasis. Indeed, the absence of functional PTEN in cancer cells leads to constitutive activation of downstream components of the PI3K pathway including the Akt and mTOR kinases. In model organisms, inactivation of these kinases can reverse the effects of PTEN loss. These data raise the possibility that drugs targeting these kinases, or PI3K itself, might have significant therapeutic activity in PTEN-null cancers. Akt kinase inhibitors are still in development; however, as a first test of this hypothesis, phase I and phase II trials of inhibitors of mTOR, namely, rapamycin and rapamycin analogs are underway.


Orthographic influences on phoneme deletion response times.
The aim of this paper is to provide further evidence that orthography plays a central role in phonemic awareness, by demonstrating an orthographic congruency effect in phoneme deletion. In four initial phoneme deletion experiments, adult participants produced the correct response more slowly with orthographically mismatched stimulus-response pairs (e.g., worth-earth) than with matched pairs (e.g., wage-age). This orthographic effect occurred with or without specific instructions to ignore spelling and when stimuli were presented with or without the to-be-deleted sound. In a final experiment, participants made more errors on complex than simple onset items, but there was no interaction with orthographic mismatch. The repeated observation of this robust orthographic effect suggests that participants are at least aware of orthography during phonemic awareness tasks, and it supports the view that phonemic awareness is directly subserved by orthography.


In vivo magnetic resonance imaging of the human limbic white matter.
The limbic system mediates memory, behavior, and emotional output in the human brain, and is implicated in the pathology of Alzheimer's disease and a wide spectrum of related neurological disorders. In vivo magnetic resonance imaging (MRI) of structural components comprising the limbic system and their interconnections via white matter pathways in the human brain has helped define current understanding of the limbic model based on the classical circuit proposed by Papez. MRI techniques, including diffusion MR imaging, provide a non-invasive method to characterize white matter tracts of the limbic system, and investigate pathological changes that affect these pathways in clinical settings. This review focuses on delineation of the anatomy of major limbic tracts in the human brain, namely, the cingulum, the fornix and fimbria, and the stria terminalis, based on in vivo MRI contrasts. The detailed morphology and intricate trajectories of these pathways that can be identified using relaxometry-based and diffusion-weighted MRI provide an important anatomical reference for evaluation of clinical disorders commonly associated with limbic pathology.


Clinician self-efficacy in initiating discussions about gestational weight gain.
To compare prenatal care providers' perceived self-efficacy in starting discussions about gestational weight gain with pregnant women under a variety of conditions of gradated difficulty, when weight gain has been in excess of current guidelines. A 42-item online questionnaire related to the known barriers to and facilitators of having discussions about gestational weight gain. Canada. Prenatal care providers were contacted through the Family Medicine Maternity Care list server of the College of Family Physicians of Canada. The 42 items were clustered into categories representing patient factors, interpersonal factors, and system factors. Participants scored their self-efficacy on a scale from 0 ("cannot do at all") to 5 ("moderately certain can do") to 10 ("highly certain can do"). The significance level was set at α = .05. Overall, clinicians rated their self-efficacy to be high, ranging from a low mean (SD) score of 5.14 (3.24) if the clinic was running late, to a high mean score of 8.97 (1.34) if the clinician could externalize the reason for undertaking the discussion. There were significant differences in self-efficacy scores within categories depending on the degree of difficulty proposed by the items in those categories. The results were inconsistent with previous studies that have demonstrated that prenatal care providers do not frequently raise the subject of excess gestational weight gain. On the one hand providers rate their self-efficacy in having these discussions to be high, but on the other hand they do not undertake the behaviour, at least according to their patients. Future research should explore this discrepancy with a view to informing interventions to help providers and patients in their efforts to address excess gestational weight gain, which is increasingly an important contributor to the obesity epidemic.


In Vivo Chondrogenesis in 3D Bioprinted Human Cell-laden Hydrogel Constructs.
The three-dimensional (3D) bioprinting technology allows creation of 3D constructs in a layer-by-layer fashion utilizing biologically relevant materials such as biopolymers and cells. The aim of this study is to investigate the use of 3D bioprinting in a clinically relevant setting to evaluate the potential of this technique for in vivo chondrogenesis. Thirty-six nude mice (Balb-C, female) received a 5- × 5- × 1-mm piece of bioprinted cell-laden nanofibrillated cellulose/alginate construct in a subcutaneous pocket. Four groups of printed constructs were used: (1) human (male) nasal chondrocytes (hNCs), (2) human (female) bone marrow-derived mesenchymal stem cells (hBMSCs), (3) coculture of hNCs and hBMSCs in a 20/80 ratio, and (4) Cell-free scaffolds (blank). After 14, 30, and 60 days, the scaffolds were harvested for histological, immunohistochemical, and mechanical analysis. The constructs had good mechanical properties and keep their structural integrity after 60 days of implantation. For both the hNC constructs and the cocultured constructs, a gradual increase of glycosaminoglycan production and hNC proliferation was observed. However, the cocultured group showed a more pronounced cell proliferation and enhanced deposition of human collagen II demonstrated by immunohistochemical analysis. In vivo chondrogenesis in a 3D bioprinted human cell-laden hydrogel construct has been demonstrated. The trophic role of the hBMSCs in stimulating hNC proliferation and matrix deposition in the coculture group suggests the potential of 3D bioprinting of human cartilage for future application in reconstructive surgery.


Proteomic changes to immune and inflammatory processes underlie lung preservation using ex vivo cytokine adsorption.
In recent years, the field of graft preservation has made considerable strides in improving outcomes related to solid organ restoration and regeneration. Ex vivo lung perfusion (EVLP) in line with the related devices and treatments has yielded promising results within preclinical and clinical studies, with the potential to improve graft quality. Its main benefit is to render marginal and declined donor lungs suitable for transplantation, ultimately increasing the donor pool available for transplantation. In addition, using such therapies in machine perfusion could also increase preservation time, facilitating logistical planning. Cytokine adsorption has been demonstrated as a potentially safe and effective therapy when applied to the EVLP circuit and post-transplantation. However, the mechanism by which this therapy improves the donor lung on a molecular basis is not yet fully understood. We hypothesized that there were characteristic inflammatory and immunomodulatory differences between the lungs treated with and without cytokine adsorption, reflecting proteomic changes in the gene ontology pathways and across inflammation-related proteins. In this study, we investigate the molecular mechanisms and signaling pathways of how cytokine adsorption impacts lung function when used during EVLP and post-transplantation as hemoperfusion in a porcine model. Lung tissues during EVLP and post-lung transplantation were analyzed for their proteomic profiles using mass spectrometry. We found through gene set enrichment analysis that the inflammatory and immune processes and coagulation pathways were significantly affected by the cytokine treatment after EVLP and transplantation. In conclusion, we showed that the molecular mechanisms are using a proteomic approach behind the previously reported effects of cytokine adsorption when compared to the non-treated transplant recipients undergoing EVLP.


Distribution of Ixodes scapularis in Northwestern Ontario: Results from Active and Passive Surveillance Activities in the Northwestern Health Unit Catchment Area.
The range of Ixodes scapularis is expanding in Ontario, increasing the risk of Lyme disease. As an effective public health response requires accurate information on disease distribution and areas of risk, this study aims to establish the geographic distribution of I. scapularis and its associated pathogen, B. burgdorferi, in northwestern Ontario. We assessed five years of active and passive tick surveillance data in northwestern Ontario. Between 2013 and 2017, 251 I. scapularis were submitted through passive surveillance. The submission rate increased over time, and the proportion infected with B. burgdorferi was 13.5%. Active tick surveillance from 2014 to 2016 found few I. scapularis specimens. In 2017, 102 I. scapularis were found in 10 locations around the city of Kenora; 60% were infected with B. burgdorferi, eight tested positive for A. phagocytophilum, and one for POWV. I. scapularis ticks were found in 14 locations within the Northwestern Health Unit area, with seven locations containing B. burgdorferi-positive ticks. We found abundant I. scapularis populations in the southern portion of northwestern Ontario and northward expansion is expected. It is recommended that I. scapularis populations continue to be monitored and mitigation strategies should be established for rural northern communities.