AT2 receptors cross talk with AT1 receptors through a nitric oxide- and RhoA-dependent mechanism resulting in decreased phospholipase D activity.
ANG II activation of phospholipase D (PLD) is required for ERK and NAD(P)H oxidase activation, both of which are involved in hypertension. Previous findings demonstrate that ANG II stimulates PLD activity through AT(1) receptors in a RhoA-dependent mechanism. Additionally, endogenous AT(2) receptors in preglomerular smooth muscle cells attenuate ANG II-mediated PLD activity. In the present study, we examined the signal transduction mechanisms used by endogenous AT(2) receptors to modulate ANG II-induced PLD activity through either PLA(2) generation of lysophosphatidylethanolamine or Galpha(i)-mediated generation of nitric oxide (NO) and interaction with RhoA. Blockade of AT(2) receptors, Galpha(i) and NO synthase, but not PLA(2), enhanced ANG II-mediated PLD activity in cells rich in, but not poor in, AT(2) receptors. Moreover, NO donors, a direct activator of guanylyl cyclase and a cGMP analog, but not lysophosphatidylethanolamine, inhibited ANG II-mediated PLD activity, whereas an inhibitor of guanylyl cyclase augmented ANG II-induced PLD activity. AT(2) receptor- and NO-mediated attenuation of ANG II-induced PLD activity was completely lost in cells transfected with S188A RhoA, which cannot be phosphorylated on serine 188. Therefore, our data indicate that AT(2) receptors activate Galpha(i), subsequently stimulating NO synthase and leading to increased soluble guanylyl cyclase activity, generation of cGMP, and activation of a protein kinase, resulting in phosphorylation of RhoA on serine 188. Furthermore, because AT(2) receptors inhibit AT(1) receptor signaling to PLD via modulating RhoA activity, AT(2) receptor signaling can potentially regulate multiple vasoconstrictive signaling systems through inactivating RhoA.


HIV is an important risk factor for human papillomavirus types 16 and 18 seropositivity among sexually active men who have sex with men.
The aim of this study was to investigate whether HIV infection is a main risk factor for human papillomavirus (HPV)-16 and HPV-18 seropositivity in men who have sex with men (MSM), and what other risk factors are associated with HPV-16 and HPV-18 seropositivity in this population. Men who have sex with men visiting a sexually transmitted infection (STI) clinic in Amsterdam in 2008 to 2009 answered questions concerning demographics and sexual behavior. Sera were tested for HPV antibodies to the major HPV capsid protein L1 by Luminex-based multiplex serology. As it is known that site of exposure is associated with seropositivity, this analysis was restricted to MSM who reported receptive anal sex during the preceding 6 months. Using multivariable logistic regression, we examined whether HIV was associated with HPV serostatus. Included in the study were 415 HIV-negative and 205 HIV-positive MSM reporting receptive anal sex. Median age of the study population was 39 years (interquartile range, 31-44). Human papillomavirus seroprevalence differed significantly between HIV-negative and HIV-positive MSM: 31% versus 65% (P < 0.001) for HPV-16 and 28% versus 51% (P < 0.001) for HPV-18. After adjusting for important risk factors HPV-16 (adjusted odds ratio, 2.80; 95% confidence interval, 1.75-4.49) and HPV-18 (adjusted odds ratio, 1.78; 95% confidence interval, 1.11-2.85), seropositivity was significantly more common in HIV-positive than in HIV-negative MSM. We could not identify other consistent risk factors for HPV-16 and HPV-18 seropositivity. HIV infection is an important risk factor for HPV-16 and HPV-18 seropositivity among MSM reporting receptive anal sex in the preceding 6 months.


Caregiver resilience in palliative care: a research protocol.
To describe a research protocol designed to formulate a conceptual framework of informal caregiver resilience in palliative care. Resilience is the ability to adapt or to improve one's own conditions following experiences of adversity. The end-of-life care provided by informal caregivers is a form of adversity because it entails objective difficulties, emotional involvement and deep levels of introspection that have been stimulated by the death event. Resilience has not yet been addressed in association with end-of-life care. This is a multicentre cross-sectional study. We will administer a questionnaire to a sample of informal end-of-life caregivers to collect data about the main psychological, behavioural and healthcare factors that impact resilience. Data analysis will include descriptive and correlational statistical techniques, multiple linear regressions and structural equation modelling. Data will be collected in multiple palliative care centres and statistical analysis will be carried out using software: SPSS version 19.0 and MPlus version 7.3. The study is supported by a grant from the Centre of Excellence for Nursing Scholarship in Italy (Research Grant number 2.13.10) that was awarded in March 2013. The study seeks to identify the predictive, mediating and moderating roles of select variables: caregivers' self-efficacy, burdens of caregiving, depression and resilience. The results of this analysis will impact the theoretical study of resilience in palliative care and will have practical implications for interventions aimed at supporting caregivers through healthcare teams.


Opportunities and challenges in modeling emerging infectious diseases.
The term "pathogen emergence" encompasses everything from previously unidentified viruses entering the human population to established pathogens invading new populations and the evolution of drug resistance. Mathematical models of emergent pathogens allow forecasts of case numbers, investigation of transmission mechanisms, and evaluation of control options. Yet, there are numerous limitations and pitfalls to their use, often driven by data scarcity. Growing availability of data on pathogen genetics and human ecology, coupled with computational and methodological innovations, is amplifying the power of models to inform the public health response to emergence events. Tighter integration of infectious disease models with public health practice and development of resources at the ready has the potential to increase the timeliness and quality of responses.


Differential Expression and Clinical Significance of DNA Methyltransferase 3B (DNMT3B), Phosphatase and Tensin Homolog (PTEN) and Human MutL Homologs 1 (hMLH1) in Endometrial Carcinomas.
BACKGROUND The aim of this study was to investigate the expression and the clinicopathologic significance of DNA methyltransferase 3B (DNMT3B), phosphatase and tensin homolog (PTEN) and human MutL homologs 1 (hMLH1) in endometrial carcinomas between Han and Uygur women in Xinjiang. MATERIAL AND METHODS The expression of DNMT3B, PTEN, and hMLH1 in endometrial carcinomas were assessed by immunohistochemistry, followed by an analysis of their relationship to clinical-pathological features and prognosis. RESULTS There were a 61.7% (95/154) overexpression of DNMT3B, 50.0% (77/154) loss of PTEN expression and 18.2% (28/154) loss of hMLH1 expression. The expression of DNMT3B and PTEN in endometrial carcinomas was statistically significantly different between Uygur women and Han women (p=0.001, p=0.010, respectively). DNMT3B expression was statistically significant based on the grade of endometrial carcinomas (p=0.031). PTEN loss was statistically significant between endometrioid carcinomas (ECs) and non endometrioid carcinomas (NECs) (p=0.040). DNMT3B expression was statistically significant in different myometrial invasion groups in Uygur women (p=0.010). Furthermore, the correlation of DNMT3B and PTEN expression was significant in endometrial carcinomas (p=0.021). PTEN expression was statistically significant in the overall survival (OS) rate of women with endometrial cancers (p=0.041). CONCLUSIONS Our findings suggest that PTEN and DNMT3B possess common regulation features as well as certain ethnic differences in expression between Han women and Uygur women. An interaction may exist in the pathogenesis of endometrial carcinoma. DNMT3B was expressed differently in cases of myometrial invasion and PTEN was associated with OS, which suggested that these molecular markers may be useful in the evaluation of the biological behavior of endometrial carcinomas and may be useful indicators of prognosis in women with endometrial carcinomas.


An alternate method for estimation of cell growth kinetics from batch cultures.
An alternative to estimation of cell growth kinetics via continuous culture experiments is proposed in this article. The method employed is based on batch culture experiments with very small inocula (initial cell concentrations being typically less than 5000 cells/mL). Such low initial cell concentrations result in extended exponential cell growth phase during which culture conditions remain unchanged, thereby permitting precise estimation of specific cell growth rates from batch experiments especially for fast-growing microorganisms such as Bacillus species. The effectiveness and utility of this approach are demonstrated via several experiments conducted with a wild-type strain (Bacillus subtilis TN106) and a recombinant strain (B. subtilis TN106[pAT5]). True establishment of exponential growth phase requires insignificant variance of most of the culture conditions during the initial growth phase. Satisfaction of this requirement is demonstrated for microbial systems investigated here. This approach is especially well suited for recombinant microorganisms containing segregationally unstable plasmids, since estimation of growth kinetics of these from continuous cultures is very difficult and highly unreliable due to continual reversion of recombinant ceils to plasmid-free host cells unless some selection pressure is applied at levels sufficient to keep the presence of plasmid-free cells minimal.


Width and neurophysiologic properties of tissue bridges predict recovery after cervical injury.
To assess whether preserved dorsal and ventral midsagittal tissue bridges after traumatic cervical spinal cord injury (SCI) encode tract-specific electrophysiologic properties and are predictive of appropriate recovery. In this longitudinal study, we retrospectively assessed MRI scans at 1 month after SCI that provided data on width and location (dorsal vs ventral) of midsagittal tissue bridges in 28 tetraplegic patients. Regression analysis assessed associations between midsagittal tissue bridges and motor- and sensory-specific electrophysiologic recordings and appropriate outcome measures at 12 months after SCI. Greater width of dorsal midsagittal tissue bridges at 1 month after SCI identified patients who were classified as being sensory incomplete at 12 months after SCI (p = 0.025), had shorter sensory evoked potential (SEP) latencies (r = -0.57, p = 0.016), and had greater SEP amplitudes (r = 0.61, p = 0.001). Greater width of dorsal tissue bridges predicted better light-touch score at 12 months (r = 0.40, p = 0.045) independently of baseline clinical score and ventral tissue bridges. Greater width of ventral midsagittal tissue bridges at 1 month identified patients who were classified as being motor incomplete at 12 months (p = 0.002), revealed shorter motor evoked potential (MEP) latencies (r = -0.54, p = 0.044), and had greater ratios of MEP amplitude to compound muscle action potential amplitude (r = 0.56, p = 0.005). Greater width of ventral tissue bridges predicted better lower extremity motor scores at 12 months (r = 0.41, p = 0.035) independently of baseline clinical score and dorsal tissue bridges. Midsagittal tissue bridges, detectable early after SCI, underwrite tract-specific electrophysiologic communication and are predictors of appropriate sensorimotor recovery. Neuroimaging biomarkers of midsagittal tissue bridges may be integrated into the diagnostic workup, prediction of recovery, and patients' stratification in clinical trials.


Amino acid profile and aromatic amino acid concentration in total parenteral nutrition: effect on growth, protein metabolism and aromatic amino acid metabolism in the neonatal piglet.
1. The protein and amino acid utilization of two commercially available amino acid solutions, one egg-patterned (Vamin), the other human-milk-patterned (Vaminolact), were studied in piglets receiving total parenteral nutrition. It was hypothesized that Vaminolact was deficient in total aromatic amino acids, so a third group received a human-milk-patterned amino acid solution with added phenylalanine. 2. The piglets were on total parenteral nutrition for 8 days from day 2 or 3 of life. They all received a total energy intake of 1040 kJ day-1 kg-1 with macronutrient intakes of 14.6 g of amino acid, 27.4 g of glucose and 9.4 g of fat day-1 kg-1. 3. Nitrogen balances were performed on days 3-8 of total parenteral nutrition. On day 8 a primed constant infusion of (1-14C]-phenylalanine was given to measure phenylalanine flux and fractional conversion to tyrosine. Transamination catabolites of phenylalanine and tyrosine were measured in urine on day 7. 4. The piglets receiving Vaminolact gained significantly less weight (0.86 kg compared with 1.18 kg for Vamin and 1.20 kg for phenylalanine-supplemented Vaminolact; P < 0.02) and nitrogen (1435 mg day-1 kg-1 compared with 1601 mg and 1836 mg day-1 kg-1 for the other groups; P < 0.0001). 5. The piglets receiving Vamin had high plasma phenylalanine levels (2234 mumol/l compared with 156 mumol/l for Vaminolact and 399 mumol for phenylalanine-supplemented vaminolact; P < 0.0001). Those receiving Vamin also had an elevated excretion of phenylalanine transamination metabolites and low plasma lysine levels. Phenylalanine flux was highest in the Vamin group, intermediate in the phenylalanine-supplemented Vaminolact group and lowest in the Vaminolact group. 6. We conclude that Vaminolact is limiting in aromatic amino acids and that the addition of phenylalanine to the level in Vamin significantly improves growth and nitrogen retention; however, increasing the phenylalanine content of total parenteral nutrition is not the most metabolically suitable way to provide aromatic amino acids in neonatal total parenteral nutrition.


Dissecting the steps of CO₂ reduction: 1. The interaction of CO and CO₂ with γ-Al₂O₃: an in situ FTIR study.
The adsorption of CO2 and CO was investigated on a pure γ-Al2O3 support material that has been used in Pd and Ru catalysts for the reduction of CO2. The adsorption of CO2 resulted in the formation of carbonates, bicarbonates and linearly adsorbed CO2 species. The amount and the nature of the adsorbed species were dependent on the annealing temperature of the alumina support. On γ-Al2O3 annealed at 473 K mostly bicarbonates formed, while no adsorbed CO2 was seen on this highly hydroxylated surface. With increasing calcination temperature the amount of both surface carbonates and linearly adsorbed CO2 increased, but still the most abundant surface species were bicarbonates. Surface carbonates and adsorbed CO2 can readily be removed from the alumina surface, while bicarbonates are stable to elevated temperatures. The interaction of CO with γ-Al2O3 is much weaker than that of CO2. At room temperature CO adsorbs only on Lewis acid sites, and can be readily removed by evacuation. At 100 K CO can probe different defect sites on the alumina surface. Under no conditions we have observed the formation of any carbonates or bicarbonates upon the interaction of CO with the pure alumina support. In co-adsorption experiments CO competes for adsorption sites with the linearly adsorbed CO2 on the 773 K-annealed γ-Al2O3 surface, but it does not result in the desorption of CO2, rather in the increased production of weakly held carbonates. After the removal of adsorbed CO, CO2 moves back to its original adsorption sites, i.e., Lewis acidic Al(3+) centers. The exposure of a CO2-saturated γ-Al2O3 to H2O did not affect any of the adsorbed surface species. The findings of this study will be used to rationalize the results of our ongoing in situ and in operando studies on the reduction of CO2 on supported Pd and Ru catalysts.


Decreased mRNA expression of netrin-G1 and netrin-G2 in the temporal lobe in schizophrenia and bipolar disorder.
The membrane-bound axon guidance molecules netrin-G1 (NTNG1) and netrin-G2 (NTNG2) play a role in synaptic formation and maintenance. Non-coding single nucleotide polymorphisms (SNPs) in both genes have been reported to be associated with schizophrenia. The main aim of this study was to determine if NTNG1 and NTNG2 mRNA expression is altered in schizophrenia or bipolar disorder, and/or influenced by disease-associated SNPs. NTNG1 and NTNG2 mRNAs were examined in the medial and inferior temporal lobe using in situ hybridization and RT-PCR in the Stanley Medical Research Institute array collection, and in rat hippocampus during development and after antipsychotic administration. NTNG1 mRNA isoforms were also examined during human brain development. For NTNG1, the G1c isoform was reduced in bipolar disorder and with a similar trend in schizophrenia; expression of four other NTNG1 isoforms was unchanged. In both schizophrenia and bipolar disorder, NTNG2 mRNA was reduced in CA3, with reductions also found in CA4 and perirhinal cortex in bipolar disorder. The SNPs did not affect NTNG1 or NTNG2 mRNA expression. Both NTNG1 and NTNG2 mRNAs were developmentally regulated, and were unaltered by haloperidol, but NTNG2 mRNA was modestly increased by clozapine. These data implicate NTNG1 and NTNG2 in the pathophysiology of schizophrenia and bipolar disorder, but do not support the hypothesis that altered mRNA expression is the mechanism by which genetic variation of NTNG1 or NTNG2 may confer disease susceptibility.


Recent Trends in Unpasteurized Fluid Milk Outbreaks, Legalization, and Consumption in the United States.
Determining the potential risk of foodborne illness has become critical for informing policy decisions, due to the increasing availability and popularity of unpasteurized (raw) milk. Trends in foodborne illnesses reported to the Centers for Disease Control in the United States from 2005 to 2016 were analyzed, with comparison to state legal status and to consumption, as estimated by licensing records. The rate of unpasteurized milk-associated outbreaks has been declining since 2010, despite increasing legal distribution. Controlling for growth in population and consumption, the outbreak rate has effectively decreased by 74% since 2005. Studies of the role of on-farm food safety programs to promote the further reduction of unpasteurized milk outbreaks should be initiated, to investigate the efficacy of such risk management tools.


Dark chocolate attenuates intracellular pro-inflammatory reactivity to acute psychosocial stress in men: A randomized controlled trial.
Flavanol-rich dark chocolate consumption relates to lower risk of cardiovascular mortality, but underlying mechanisms are elusive. We investigated the effect of acute dark chocolate consumption on inflammatory measures before and after stress. Healthy men, aged 20-50years, were randomly assigned to a single intake of either 50g of flavanol-rich dark chocolate (n=31) or 50g of optically identical flavanol-free placebo-chocolate (n=34). Two hours after chocolate intake, both groups underwent the 15-min Trier Social Stress Test. We measured DNA-binding-activity of the pro-inflammatory transcription factor NF-κB (NF-κB-BA) in peripheral blood mononuclear cells, as well as plasma and whole blood mRNA levels of the pro-inflammatory cytokines IL-1β and IL-6, and the anti-inflammatory cytokine IL-10, prior to chocolate intake as well as before and several times after stress. We also repeatedly measured the flavanol epicatechin and the stress hormones epinephrine and cortisol in plasma and saliva, respectively. Compared to the placebo-chocolate-group, the dark-chocolate-group revealed a marginal increase in IL-10 mRNA prior to stress (p=0.065), and a significantly blunted stress reactivity of NF-κB-BA, IL-1β mRNA, and IL-6 mRNA (p's⩽0.036) with higher epicatechin levels relating to lower pro-inflammatory stress reactivity (p's⩽0.033). Stress hormone changes to stress were controlled. None of the other measures showed a significant chocolate effect (p's⩾0.19). Our findings indicate that acute flavanol-rich dark chocolate exerts anti-inflammatory effects both by increasing mRNA expression of the anti-inflammatory cytokine IL-10 and by attenuating the intracellular pro-inflammatory stress response. This mechanism may add to beneficial effects of dark chocolate on cardiovascular health.


Relation between central adiposity and cognitive function in the Maine-Syracuse Study: attenuation by physical activity.
Previous studies have demonstrated a relationship between central adiposity and cognitive function. However, only some of these studies have adjusted for cardiovascular risk factors and cardiovascular disease, and none have also adjusted for physical activity level. The purpose of the study was to examine the association between anthropometric measures of central adiposity (waist circumference and waist/hip ratio) and cognitive functioning with adjustment for cardiovascular disease risk factors and physical activity. Participants were 917 stroke- and dementia-free community-dwelling adults (59% women) in the Maine-Syracuse Study. The design was cross-sectional. Outcome measures included tests from the Wechsler Adult Intelligence Scale, the Halstead-Reitan Neuropsychological Battery, the Wechsler Memory Scale Revised, and the Mini-Mental State Examination. Waist circumference and waist/hip ratio were inversely related to multiple cognitive domains with adjustment for age, education, gender, and number of prior exams. For example, a 20-cm increment in waist circumference was associated with a 0.14 SD decrement in the Global Composite score. These relations were attenuated with adjustment for cardiovascular disease risk factors. However, with further adjustment for physical activity level, only waist circumference remained significantly associated with performance on the Similarities test. Waist circumference and waist/hip ratio are inversely related to cognitive function. Measures of central adiposity predict cognitive function independently of associated cardiovascular risk factors and events; however, the association between central adiposity and cognitive function is attenuated, to a large extent, by adjustment for physical activity level. Physical activity is an important covariate in studies relating measures of central adiposity to cognition.


MinCDE exploits the dynamic nature of FtsZ filaments for its spatial regulation.
In Escherichia coli, a contractile ring (Z-ring) is formed at midcell before cytokinesis. This ring consists primarily of FtsZ, a tubulin-like GTPase, that assembles into protofilaments similar to those in microtubules but different in their suprastructures. The Min proteins MinC, MinD, and MinE are determinants of Z-ring positioning in E. coli. MinD and MinE oscillate from pole to pole, and genetic and biochemical evidence concludes that MinC positions the Z-ring by coupling its assembly to the oscillations by direct inhibitory interaction. The mechanism of inhibition of FtsZ polymerization and, thus, positioning by MinC, however, is not understood completely. Our in vitro reconstitution experiments suggest that the Z-ring consists of dynamic protofilament bundles in which monomers constantly are exchanged throughout, stochastically creating protofilament ends along the length of the filament. From the coreconstitution of FtsZ with MinCDE, we propose that MinC acts on the filaments in two ways: by increasing the detachment rate of FtsZ-GDP within the filaments and by reducing the attachment rate of FtsZ monomers to filaments by occupying binding sites on the FtsZ filament lattice. Furthermore, our data show that the MinCDE system indeed is sufficient to cause spatial regulation of FtsZ, required for Z-ring positioning.


Adverse effects of imidocarb dipropionate (Imizol) in a dog.
One of 13 healthy dogs used in a pharmacokinetic study of imidocarb dipropionate died due to difficulty in breathing, tachycardia, weakness and profuse diarrhoea. Autopsy findings showed marked pulmonary congestion and oedema. Kidneys were grossly enlarged and markedly congested with extensive haemorrhage in the cortex and medulla. Marked tubulonephrosis was also exhibited microscopically. Liver and spleen were moderately enlarged and congested. The adverse effects of imidocarb may be due to excessive acetylcholine action.


Language, Motor, and Cognitive Outcomes of Toddlers Who Were Born Preterm.
Purpose The purpose of this study was to examine the language, motor, and cognitive abilities of children born preterm in four categories: (a) healthy preterm infants, (b) infants of diabetic mothers, (c) infants with respiratory distress syndrome, and (d) infants with chronic lung disease when the children were 30 months, uncorrected age. Comorbidity of language, motor, and cognitive skills was examined, along with predictor variables. Method A total of 148 children who were born preterm participated and were assessed using bivariate tests and logistic regression on standardized assessment scores. Results Controlling for the children's gestational age (GA), overall language ability was significantly lower in the infants of diabetic mothers group compared to the healthy preterm infant group, and expressive language skills were significantly lower for the chronic lung disease group than the respiratory distress syndrome group. The children with language delays on at least one measure were significantly more likely to have cognitive, motor, or both delays. Lower maternal education was a significant predictor for language and cognitive delays, and younger GA was a significant predictor for language, motor, and cognitive delays. Conclusion Assessment of the preterm infant from a biosystems approach allows the speech-language pathologist to take into consideration maternal education, diagnosis at preterm birth, and GA, which were found to impact the language, motor, and cognitive outcomes of children born preterm. Our findings further reinforce the concept of the whole child in that children born preterm who display language delays should be screened for co-occurring motor and/or cognitive delays.


Tumor-specific expression of the RGD-alpha3(IV)NC1 domain suppresses endothelial tube formation and tumor growth in mice.
Angiogenesis plays an essential role in tumor growth. This study investigated expression of the noncollagenous domain of alpha3(IV) collagen (alpha3(IV)NC1) transduced into tumors and its inhibition of tumor growth. We hypothesized that if a human telomerase reverse transcriptase (hTERT) promoter-driven RGD motif containing alpha3(IV)NC1 (hTERT/RGD-alpha3(IV)NC1) were expressed in telomerase-expressing tumor cells, it would inhibit tumor growth by its anti-angiogenic property. Adenoviral transduction of hTERT/RGD-alpha3(IV)NC1 expressed RGD-alpha3(IV)NC1 in hTERT-positive tumor cell lines. However, hTERT/RGD-alpha3(IV)NC1 did not express RGD-alpha3(IV)NC1 in hTERT-negative cells such as keratinocytes and fibroblasts. The secreted RGD-alpha3(IV)NC1 in the conditioned medium from tumor cells inhibited cell proliferation as well as tube formation in cultured endothelial cells, but had no effect on other types of cells. In an in vivo model, adenoviral hTERT/RGD-alpha3(IV)NC1 gene therapy showed limited expression of RGD-alpha3(IV)NC1 in tumors and resulted in a significant decrease of vessel density in tumors. The growth of subcutaneous (s.c.) tumors in nude mice was significantly suppressed by treatment with hTERT/RGD-alpha3(IV)NC1. In addition, long-term inhibition of tumor growth was achieved by intermittent administration of hTERT/RGD-alpha3(IV)NC1. In conclusion, our findings demonstrate that tumor-specific anti-angiogenic gene therapy utilizing RGD-alpha3(IV)NC1 under the hTERT promoter inhibited angiogenesis in tumors, resulting in an antitumor effect.


Post-Procedural Dabigatran Versus Interrupted Warfarin Therapy Following Catheter Ablation for Atrial Fibrillation.
Patients undergoing catheter ablation for atrial fibrillation (AF) are at a higher risk of thromboembolic events post-procedure and therefore require therapeutic anticoagulation after ablation. Anticoagulation strategies include performing the procedure on or off therapeutic warfarin, though the latter approach requires post-procedure bridging therapy with low molecular-weight heparin (LMWH) until a therapeutic INR is achieved. The purpose of this study is to compare the safety and efficacy of post-ablation dabigatran as compared to warfarin with LMWH bridging. We performed a single-center retrospective analysis of consecutive patients who underwent catheter ablation for AF between January 2010 and December 2012 and received either post-procedure warfarin with a LMWH bridge or dabigatran. Warfarin was started the night of ablation; LMWH was started the next morning and continued until the INR was ≥ 2.0. Dabigatran was started the morning post-ablation. The analysis included 324 patients. Of these, mean age was 60 ± 9 years, 78% were male, 81% had CHADS2 scores of 0 or 1, and 181 (56%) received dabigatran post-ablation. Patients who received dabigatran had lower CHADS2 scores and were more likely to be in NYHA Class I. At 30-days post-procedure, there were 0 thromboembolic or bleeding complications in the dabigatran group versus 4 (2.8%) in the warfarin group (p=0.037). There were no deaths in either group at 30 days post-ablation. Post-ablation dabigatran appears safe and efficacious compared to an interrupted warfarin strategy with LMWH bridging.


The physiological requirements of Soccer refereeing.
The movement patterns and heart rate responses of Soccer referees during matches were examined. A movement analysis was performed using a grid method and subjects wore a PE 3000 heart rate monitor during the match. The mean distance (+/- SD) covered was 9,408 m (+/- 838m) which comprised: walking (18.9%), jogging (46.6%), running/striding (12.1%), sprinting (6.2%) and backwards movement (16.2%). If walking and jogging are pooled as low intensity activity and high intensity work is defined as running/striding and sprinting then the majority of distance was covered by low intensity activity (65.5%). No differences in the total distance covered during the two halves was evident. However, in the second half the subjects walked more than in the first half (p < 0.01), while they ran/strode more in the first when compared to the second half (p < 0.01). The subjects' mean heart rate during the first and second halves was not significantly different and were 163 and 162 beats per minute (b.min-1) respectively. If the theoretical maximum heart rate for each subject (220-age) is used, the major percentage of the time was spent at heart rates above 85% HRmax. Based upon the distance results of this study, the major energy source for Soccer refereeing would appear to be the aerobic system with the anaerobic system contributing to ATP production to a lesser extent. The results of this study suggest that refereeing at a high level places a significant physiological demand upon these athletes; they therefore require specialised assessment and training.


Lidar backscatter signal recovery from phototransistor systematic effect by deconvolution.
Backscatter lidar detection systems have been designed and integrated at NASA Langley Research Center using IR heterojunction phototransistors. The design focused on maximizing the system signal-to-noise ratio rather than noise minimization. The detection systems have been validated using the Raman-shifted eye-safe aerosol lidar (REAL) at the National Center for Atmospheric Research. Incorporating such devices introduces some systematic effects in the form of blurring to the backscattered signals. Characterization of the detection system transfer function aided in recovering such effects by deconvolution. The transfer function was obtained by measuring and fitting the system impulse response using single-pole approximation. An iterative deconvolution algorithm was implemented in order to recover the system resolution, while maintaining high signal-to-noise ratio. Results indicated a full recovery of the lidar signal, with resolution matching avalanche photodiodes. Application of such a technique to atmospheric boundary and cloud layers data restores the range resolution, up to 60 m, and overcomes the blurring effects.


Genome-wide nucleosome map and cytosine methylation levels of an ancient human genome.
Epigenetic information is available from contemporary organisms, but is difficult to track back in evolutionary time. Here, we show that genome-wide epigenetic information can be gathered directly from next-generation sequence reads of DNA isolated from ancient remains. Using the genome sequence data generated from hair shafts of a 4000-yr-old Paleo-Eskimo belonging to the Saqqaq culture, we generate the first ancient nucleosome map coupled with a genome-wide survey of cytosine methylation levels. The validity of both nucleosome map and methylation levels were confirmed by the recovery of the expected signals at promoter regions, exon/intron boundaries, and CTCF sites. The top-scoring nucleosome calls revealed distinct DNA positioning biases, attesting to nucleotide-level accuracy. The ancient methylation levels exhibited high conservation over time, clustering closely with modern hair tissues. Using ancient methylation information, we estimated the age at death of the Saqqaq individual and illustrate how epigenetic information can be used to infer ancient gene expression. Similar epigenetic signatures were found in other fossil material, such as 110,000- to 130,000-yr-old bones, supporting the contention that ancient epigenomic information can be reconstructed from a deep past. Our findings lay the foundation for extracting epigenomic information from ancient samples, allowing shifts in epialleles to be tracked through evolutionary time, as well as providing an original window into modern epigenomics.


Effectiveness of breastfeeding education on the weight of child and self-efficacy of mothers - 2011.
Breastfeeding is the most natural and essential way for feeding newborn babies. This is an ideal approach for physical and emotional development of babies, as well as for the recovery of mothers. This study was aimed to determine the effect of breastfeeding education based on the health belief model (HBM) toward primiparous women. In a case-control group, quasi-experimental study, 88 subjects were allocated in control and experimental groups. Subjects who were assigned to the experimental group were provided a program consisting of group education based on HBM during their prenatal period. Instrument for data gathering was made by the researchers and standard questionnaire from Dennis and Faux for Breastfeeding Self-efficacy Scale (BSES). Baseline interviews were conducted before delivery and follow-up visits were conducted after 30 days and at the fourth month after delivery. Data were analyzed using SPSS (version 16) with c(2), independent sample t-tests, and paired t-test. Mean age of pregnant women who participated in the study was 22 ± 3.29 years. After the program, the experimental group had significantly better scores in terms of self-efficacy, knowledge, and attitude scores statistically. In the fourth month, the mean of child weight in the experimental group was significantly higher than that of the control group (P=0.001) and exclusive breastfeeding was significantly higher than in the control group (P=0.007). Prenatal education in this study based on HBM was successful, and knowledge, attitude, self-efficacy, and related indicators improved. The necessity of producing standard education package and education of pregnant mothers, especially in their first pregnancy, by health professionals is perceived.


Relaxation for depression.
Many members of the public have negative attitudes towards antidepressants. Psychological interventions are more acceptable but require considerable therapist training. Acceptable psychological interventions that require less training and skill are needed to ensure increased uptake of intervention. A potential intervention of this sort is relaxation techniques. To determine whether relaxation techniques reduce depressive symptoms and improve response/remission. The register of trials kept by the Cochrane Collaboration Depression, Anxiety and Neurosis Group was searched up to February 2008. We also searched the reference lists of included studies. Studies were included if they were randomised or quasi-randomised controlled trials of relaxation techniques (progressive muscle relaxation, relaxation imagery, autogenic training) in participants diagnosed with depression or having a high level of depression symptoms. Self-rated and clinician-rated depression scores and response/remission were the primary outcomes. Two reviewers selected the trials, assessed the quality and extracted trial and outcome data, with discrepancies resolved by consultation with a third. Trial authors were approached for missing data where possible and missing data were estimated or imputed in some cases. Continuous measures were summarised using standardised mean differences and dichotomous outcomes by risk ratios. There were 15 trials with 11 included in the meta-analysis. Five trials showed relaxation reduced self-reported depression compared to wait-list, no treatment, or minimal treatment post intervention (SMD -0.59 (95% CI -0.94 to -0.24)). For clinician-rated depression, two trials showed a non-significant difference in the same direction (SMD -1.35 (95% CI -3.06 to 0.37)).Nine trials showed relaxation produced less effect than psychological (mainly cognitive-behavioural) treatment on self-reported depression (SMD = 0.38 (95% CI 0.14 to 0.62)). Three trials showed no significant difference between relaxation and psychological treatment on clinician-rated depression at post intervention (SMD 0.29 (95% CI -0.18 to 0.75)).Inconsistent effects were found when comparing relaxation training to medication and there were few data available comparing relaxation with complementary and lifestyle treatments. Relaxation techniques were more effective at reducing self-rated depressive symptoms than no or minimal treatment. However, they were not as effective as psychological treatment. Data on clinician-rated depressive symptoms were less conclusive. Further research is required to investigate the possibility of relaxation being used as a first-line treatment in a stepped care approach to managing depression, especially in younger populations and populations with subthreshold or first episodes of depression.


Disparities in breast screening, stage at diagnosis, cancer treatment and the subsequent risk of cancer death: a retrospective, matched cohort of aboriginal and non-aboriginal women with breast cancer.
Australia's Aboriginal and Torres Strait Islander women have poorer survival and twice the disease burden from breast cancer compared to other Australian women. These disparities are influenced, but not fully explained, by more diagnoses at later stages. Incorporating breast screening, hospital and out of hospital treatment and cancer registry records into a person-linked data system can improve our understanding of breast cancer outcomes. We focussed one such system on a population-based cohort of Aboriginal women in South Australia diagnosed with breast cancer and a matched cohort of non-Aboriginal women with breast cancer. We quantify Aboriginal and non-Aboriginal women's contact with publicly funded screening mammograms; quantify exposure to a selection of cancer treatment modalities; then assess the relationship between screening, treatment and the subsequent risk of breast cancer death. Breast cancers registered among Aboriginal women in South Australia in 1990-2010 (N = 77) were matched with a random selection of non-Aboriginal women by birth and diagnostic year, then linked to screening records, and treatment 2 months before and 13 months after diagnosis. Competing risk regression summarised associations of Aboriginality, breast screening, cancer stage and treatment with risk of breast cancer death. Aboriginal women were less likely to have breast screening (OR = 0.37, 95%CIs 0.19-0.73); systemic therapies (OR = 0.49, 95%CIs 0.24-0.97); and, surgical intervention (OR = 0.35, 95%CIs 0.15-0.83). Where surgery occurred, mastectomy was more common among Aboriginal women (OR = 2.58, 1.22-5.46). Each of these factors influenced the risk of cancer death, reported as sub-hazard ratios (SHR). Regional spread disease (SHR = 34.23 95%CIs 6.76-13.40) and distant spread (SHR = 49.67 95%CIs 6.79-363.51) carried more risk than localised disease (Reference SHR = 1). Breast screening reduced the risk (SHR = 0.07 95%CIs 0.01-0.83). So too did receipt of systemic therapy (SHR = 0.06 95%CIs 0.01-0.41) and surgical treatments (SHR = 0.17 95%CIs 0.04-0.74). In the presence of adjustment for these factors, Aboriginality did not further explain the risk of breast cancer death. Under-exposure to screening and treatment of Aboriginal women with breast cancers in South Australia contributed to excess cancer deaths. Improved access, utilisation and quality of effective treatments is needed to improve survival after breast cancer diagnosis.


Elucidating CO2 Chemisorption in Diamine-Appended Metal-Organic Frameworks.
The widespread deployment of carbon capture and sequestration as a climate change mitigation strategy could be facilitated by the development of more energy-efficient adsorbents. Diamine-appended metal-organic frameworks of the type diamine-M2(dobpdc) (M = Mg, Mn, Fe, Co, Ni, Zn; dobpdc4- = 4,4'-dioxidobiphenyl-3,3'-dicarboxylate) have shown promise for carbon-capture applications, although questions remain regarding the molecular mechanisms of CO2 uptake in these materials. Here we leverage the crystallinity and tunability of this class of frameworks to perform a comprehensive study of CO2 chemisorption. Using multinuclear nuclear magnetic resonance (NMR) spectroscopy experiments and van-der-Waals-corrected density functional theory (DFT) calculations for 13 diamine-M2(dobpdc) variants, we demonstrate that the canonical CO2 chemisorption products, ammonium carbamate chains and carbamic acid pairs, can be readily distinguished and that ammonium carbamate chain formation dominates for diamine-Mg2(dobpdc) materials. In addition, we elucidate a new chemisorption mechanism in the material dmpn-Mg2(dobpdc) (dmpn = 2,2-dimethyl-1,3-diaminopropane), which involves the formation of a 1:1 mixture of ammonium carbamate and carbamic acid and accounts for the unusual adsorption properties of this material. Finally, we show that the presence of water plays an important role in directing the mechanisms for CO2 uptake in diamine-M2(dobpdc) materials. Overall, our combined NMR and DFT approach enables a thorough depiction and understanding of CO2 adsorption within diamine-M2(dobpdc) compounds, which may aid similar studies in other amine-functionalized adsorbents in the future.


Taxonomic anxieties: Axis I and Axis II in prison.
This essay describes the use of the Diagnostic and Statistical Manual of Psychiatry in the prison setting. The distinction between the Axis I disorders (major mental illness) and those designated Axis II (character disorders) is explored in terms of the professional division of labor in prison and the problems posed for prison discipline by "behaviorally disturbed" inmates. Conflicts over diagnosis are placed in ethnographic and historical perspective and form the basis for a discussion of the problematic relationship between disciplinary space and issues of subjection and agency.


Impact of anti-doping education and doping control experience on anti-doping knowledge in Japanese university athletes: a cross-sectional study.
This study was conducted to elucidate the anti-doping (AD) education, doping control experience, and AD knowledge according to the World Anti-doping Code (Code) of Japanese university athletes. We collected data from 514 male athletes (Mage = 19.53 years, SD = 1.13) and 629 female athletes (Mage = 20.99 years, SD = 1.07). We asked them about their experience undergoing doping control and the AD education they had received. Then, we assessed their AD knowledge using the World Anti-Doping Agency's Athlete Learning Program about Health and AD (ALPHA) test. The results showed that 2.54% of the participants had undergone doping control. Further, 30.10% received AD education at least once, and 20.82% received AD education more than once. When comparing the ALPHA scores of athletes with/without doping test experience, we observed no significant difference. However, the ALPHA scores of athletes with/without AD education were significantly different; specifically, athletes who received AD education more than once had significantly higher ALPHA scores than non-educated athletes. These results revealed that doping control experience was not related to AD knowledge and that AD education was associated with AD knowledge, suggesting that athletes who receive AD education more than once have more accurate AD knowledge than less educated athletes on this topic. The importance of AD education in promoting understanding of AD according to the Code in sports is highlighted in this study.


The KCNQ1OT1 imprinting control region and non-coding RNA: new properties derived from the study of Beckwith-Wiedemann syndrome and Silver-Russell syndrome cases.
A cluster of imprinted genes at chromosome 11p15.5 is associated with the growth disorders, Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS). The cluster is divided into two domains with independent imprinting control regions (ICRs). We describe two maternal 11p15.5 microduplications with contrasting phenotypes. The first is an inverted and in cis duplication of the entire 11p15.5 cluster associated with the maintenance of genomic imprinting and with the SRS phenotype. The second is a 160 kb duplication also inverted and in cis, but resulting in the imprinting alteration of the centromeric domain. It includes the centromeric ICR (ICR2) and the most 5' 20 kb of the non-coding KCNQ1OT1 gene. Its maternal transmission is associated with ICR2 hypomethylation and the BWS phenotype. By excluding epigenetic mosaicism, cell clones analysis indicated that the two closely located ICR2 sequences resulting from the 160 kb duplication carried discordant DNA methylation on the maternal chromosome and supported the hypothesis that the ICR2 sequence is not sufficient for establishing imprinted methylation and some other property, possibly orientation-dependent, is needed. Furthermore, the 1.2 Mb duplication demonstrated that all features are present for correct imprinting at ICR2 when this is duplicated and inverted within the entire cluster. In the individuals maternally inheriting the 160 kb duplication, ICR2 hypomethylation led to the expression of a truncated KCNQ1OT1 transcript and to down-regulation of CDKN1C. We demonstrated by chromatin RNA immunopurification that the KCNQ1OT1 RNA interacts with chromatin through its most 5' 20 kb sequence, providing a mechanism likely mediating the silencing activity of this long non-coding RNA.


Dissociating N400 effects of prediction from association in single-word contexts.
When a word is preceded by a supportive context such as a semantically associated word or a strongly constraining sentence frame, the N400 component of the ERP is reduced in amplitude. An ongoing debate is the degree to which this reduction reflects a passive spread of activation across long-term semantic memory representations as opposed to specific predictions about upcoming input. We addressed this question by embedding semantically associated prime-target pairs within an experimental context that encouraged prediction to a greater or lesser degree. The proportion of related items was used to manipulate the predictive validity of the prime for the target while holding semantic association constant. A semantic category probe detection task was used to encourage semantic processing and to preclude the need for a motor response on the trials of interest. A larger N400 reduction to associated targets was observed in the high than the low relatedness proportion condition, consistent with the hypothesis that predictions about upcoming stimuli make a substantial contribution to the N400 effect. We also observed an earlier priming effect (205-240 msec) in the high-proportion condition, which may reflect facilitation because of form-based prediction. In summary, the results suggest that predictability modulates N400 amplitude to a greater degree than the semantic content of the context.


Integration of etched facet, electrically pumped, C-band Fabry-Pérot lasers on a silicon photonic integrated circuit by transfer printing.
We report on the heterogeneous integration of electrically pumped InP Fabry-Pérot lasers on a SOI photonic integrated circuit by transfer printing. Transfer printing is a promising micromanipulation technique that allows the heterogeneous integration of optical and electronic components realized on their native substrate onto a target substrate with efficient use of the source material, in a way that can be scaled to parallel manipulation and that allows mixing components from different sources onto the same target. We pre-process transfer printable etched facet Fabry-Pérot lasers on their native InP substrate, transfer print them into a trench defined in an SOI photonic chip and post-process the printed lasers on the target substrate. The laser facet is successfully butt-coupled to the photonic circuit using a silicon inverse taper based spot size converter. Milliwatt optical output power coupled to the Si waveguide circuit at 100 mA is demonstrated.


Multimodal classification of Alzheimer's disease and mild cognitive impairment.
Effective and accurate diagnosis of Alzheimer's disease (AD), as well as its prodromal stage (i.e., mild cognitive impairment (MCI)), has attracted more and more attention recently. So far, multiple biomarkers have been shown to be sensitive to the diagnosis of AD and MCI, i.e., structural MR imaging (MRI) for brain atrophy measurement, functional imaging (e.g., FDG-PET) for hypometabolism quantification, and cerebrospinal fluid (CSF) for quantification of specific proteins. However, most existing research focuses on only a single modality of biomarkers for diagnosis of AD and MCI, although recent studies have shown that different biomarkers may provide complementary information for the diagnosis of AD and MCI. In this paper, we propose to combine three modalities of biomarkers, i.e., MRI, FDG-PET, and CSF biomarkers, to discriminate between AD (or MCI) and healthy controls, using a kernel combination method. Specifically, ADNI baseline MRI, FDG-PET, and CSF data from 51AD patients, 99 MCI patients (including 43 MCI converters who had converted to AD within 18 months and 56 MCI non-converters who had not converted to AD within 18 months), and 52 healthy controls are used for development and validation of our proposed multimodal classification method. In particular, for each MR or FDG-PET image, 93 volumetric features are extracted from the 93 regions of interest (ROIs), automatically labeled by an atlas warping algorithm. For CSF biomarkers, their original values are directly used as features. Then, a linear support vector machine (SVM) is adopted to evaluate the classification accuracy, using a 10-fold cross-validation. As a result, for classifying AD from healthy controls, we achieve a classification accuracy of 93.2% (with a sensitivity of 93% and a specificity of 93.3%) when combining all three modalities of biomarkers, and only 86.5% when using even the best individual modality of biomarkers. Similarly, for classifying MCI from healthy controls, we achieve a classification accuracy of 76.4% (with a sensitivity of 81.8% and a specificity of 66%) for our combined method, and only 72% even using the best individual modality of biomarkers. Further analysis on MCI sensitivity of our combined method indicates that 91.5% of MCI converters and 73.4% of MCI non-converters are correctly classified. Moreover, we also evaluate the classification performance when employing a feature selection method to select the most discriminative MR and FDG-PET features. Again, our combined method shows considerably better performance, compared to the case of using an individual modality of biomarkers.


Knock-down of odr-3 and ife-2 additively extends lifespan and healthspan in C. elegans.
Genetic manipulations can ameliorate the aging process and extend the lifespan of model organisms. The aim of this research was to identify novel genetic interventions that promote both lifespan and healthspan, by combining the effects of multiple longevity-associated gene inactivations in C. elegans. For this, the individual and combined effects of the odr-3 mutation and of ife-2 and cku-70 knock-downs were studied, both in the wild type and daf-16 mutant backgrounds. We found that besides increasing the lifespan of wild type animals, the knock-down of ife-2 (starting at L4) also extends the lifespan and healthspan of long-lived odr-3 mutants. In the daf-16 background, ife-2 and odr-3 impairment exert opposing effects individually, while the daf-16; odr-3; ife-2 deficient animals show a similar lifespan and healthspan as daf-16, suggesting that the odr-3 and ife-2 effector outcomes converge downstream of DAF-16. By contrast, cku-70 knock-down did not extend the lifespan of single or double odr-3; ife-2 inactivated animals, and was slightly deleterious to healthspan. In conclusion, we report that impairment of odr-3 and ife-2 increases lifespan and healthspan in an additive and synergistic manner, respectively, and that this result is not improved by further knocking-down cku-70.


DangerTrack: A scoring system to detect difficult-to-assess regions.
Over recent years, multiple groups have shown that a large number of structural variants, repeats, or problems with the underlying genome assembly have dramatic effects on the mapping, calling, and overall reliability of single nucleotide polymorphism calls. This project endeavored to develop an easy-to-use track for looking at structural variant and repeat regions. This track, DangerTrack, can be displayed alongside the existing Genome Reference Consortium assembly tracks to warn clinicians and biologists when variants of interest may be incorrectly called, of dubious quality, or on an insertion or copy number expansion. While mapping and variant calling can be automated, it is our opinion that when these regions are of interest to a particular clinical or research group, they warrant a careful examination, potentially involving localized reassembly. DangerTrack is available at https://github.com/DCGenomics/DangerTrack.


Arsenic removal from high-arsenic water by enhanced coagulation with ferric ions and coarse calcite.
Arsenic removal from high-arsenic water in a mine drainage system has been studied through an enhanced coagulation process with ferric ions and coarse calcite (38-74 microm) in this work. The experimental results have shown that arsenic-borne coagulates produced by coagulation with ferric ions alone were very fine, so micro-filtration (membrane as filter medium) was needed to remove the coagulates from water. In the presence of coarse calcite, small arsenic-borne coagulates coated on coarse calcite surfaces, leading the settling rate of the coagulates to considerably increase. The enhanced coagulation followed by conventional filtration (filter paper as filter medium) achieved a very high arsenic removal (over 99%) from high-arsenic water (5mg/l arsenic concentration), producing a cleaned water with the residual arsenic concentration of 13 microg/l. It has been found that the mechanism by which coarse calcite enhanced the coagulation of high-arsenic water might be due to attractive electrical double layer interaction between small arsenic-borne coagulates and calcite particles, which leads to non-existence of a potential energy barrier between the heterogeneous particles.


The synergy factor: a statistic to measure interactions in complex diseases.
One challenge in understanding complex diseases lies in revealing the interactions between susceptibility factors, such as genetic polymorphisms and environmental exposures. There is thus a need to examine such interactions explicitly. A corollary is the need for an accessible method of measuring both the size and the significance of interactions, which can be used by non-statisticians and with summarised, e.g. published data. The lack of such a readily available method has contributed to confusion in the field. The synergy factor (SF) allows assessment of binary interactions in case-control studies. In this paper we describe its properties and its novel characteristics, e.g. in calculating the power to detect a synergistic effect and in its application to meta-analyses. We illustrate these functions with real examples in Alzheimer's disease, e.g. a meta-analysis of the potential interaction between a BACE1 polymorphism and APOE4: SF = 2.5, 95% confidence interval: 1.5-4.2; p = 0.0001. Synergy factors are easy to use and clear to interpret. Calculations may be performed through the Excel programmes provided within this article. Unlike logistic regression analysis, the method can be applied to datasets of any size, however small. It can be applied to primary or summarised data, e.g. published data. It can be used with any type of susceptibility factor, provided the data are dichotomised. Novel features include power estimation and meta-analysis.


Sequential expression of antigens on sexual stages of Plasmodium falciparum accessible to transmission-blocking antibodies in the mosquito.
Plasmodium falciparum gametocytes contain specific antigens, some of which (Mr 230,000, 48,000, 45,000) are expressed on the surface of the newly emerged macrogamete. A different antigen (Mr 25,000) surrounds the surface of the ookinete and, although present to some extent in the developing gametocyte, is synthesized in high quantities by the macrogamete/zygote and expressed progressively on the transforming zygote surface. These antigens are targets of transmission blocking antibodies that are effective at two distinct points after gametogenesis: fertilization of the macrogamete and ookinete to oocyst development. The antigens involved in the fertilization blockade are the Mr 48 and 45 proteins, which are expressed on the macrogamete surface. The Mr 230 K coprecipitating protein probably plays no part in transmission block. mAb directed against the Mr 25 K ookinete surface protein blocked transmission without inhibiting ookinete formation, indicating that this protein has an important role in the transformation of ookinete into oocyst. A combination of mAb recognizing different epitopes on the same protein molecule acted synergistically in inhibiting oocyst formation. Using a mixture of two blocking mAb reacting against the Mr 48/45 and 25 K proteins, respectively, an additive blocking effect could be demonstrated.


Examining brain-cognition effects of ginkgo biloba extract: brain activation in the left temporal and left prefrontal cortex in an object working memory task.
Ginkgo Biloba extract (GBE) is increasingly used to alleviate symptoms of age related cognitive impairment, with preclinical evidence pointing to a pro-cholinergic effect. While a number of behavioral studies have reported improvements to working memory (WM) associated with GBE, electrophysiological studies of GBE have typically been limited to recordings during a resting state. The current study investigated the chronic effects of GBE on steady state visually evoked potential (SSVEP) topography in nineteen healthy middle-aged (50-61 year old) male participants whilst completing an object WM task. A randomized double-blind crossover design was employed in which participants were allocated to receive 14 days GBE and 14 days placebo in random order. For both groups, SSVEP was recorded from 64 scalp electrode sites during the completion of an object WM task both pre- and 14 days post-treatment. GBE was found to improve behavioural performance on the WM task. GBE was also found to increase the SSVEP amplitude at occipital and frontal sites and increase SSVEP latency at left temporal and left frontal sites during the hold component of the WM task. These SSVEP changes associated with GBE may represent more efficient processing during WM task completion.


The effect on adipose tissue blood flow of isoenergetic meals containing different amounts and types of fat.
To investigate the factors regulating the increase in adipose tissue blood flow following meals. Eight subjects were fed three isoenergetic meals; two high-fat meals rich in either saturated or polyunsaturated fatty acids and one low-fat, high-carbohydrate meal. Blood samples were taken and adipose tissue blood flow was measured before and for 6 h after the meal. Plasma glucose, insulin, non-esterified fatty acid, total and chylomicron-triacylglycerol and catecholamine concentrations were measured. Adipose tissue blood flow rose to a peak after all three meals (P<0.05 for each). The three meals stimulated adipose tissue blood flow at similar times. There was a marked and statistically significant similarity in the time course of changes in blood flow and insulin concentrations. In contrast, noradrenaline concentrations peaked later than adipose tissue blood flow (P=0.014). Adipose tissue blood flow may be 'carbohydrate-stimulated' rather than 'fat-stimulated', with insulin having a vasodilatory role in adipose tissue as in skeletal muscle.


Genetic basis for phenotypic differences between different Toxoplasma gondii type I strains.
Toxoplasma gondii has a largely clonal population in North America and Europe, with types I, II and III clonal lineages accounting for the majority of strains isolated from patients. RH, a particular type I strain, is most frequently used to characterize Toxoplasma biology. However, compared to other type I strains, RH has unique characteristics such as faster growth, increased extracellular survival rate and inability to form orally infectious cysts. Thus, to identify candidate genes that could account for these parasite phenotypic differences, we determined genetic differences and differential parasite gene expression between RH and another type I strain, GT1. Moreover, as differences in host cell modulation could affect Toxoplasma replication in the host, we determined differentially modulated host processes among the type I strains through host transcriptional profiling. Through whole genome sequencing, we identified 1,394 single nucleotide polymorphisms (SNPs) and insertions/deletions (indels) between RH and GT1. These SNPs/indels together with parasite gene expression differences between RH and GT1 were used to identify candidate genes that could account for type I phenotypic differences. A polymorphism in dense granule protein, GRA2, determined RH and GT1 differences in the evasion of the interferon gamma response. In addition, host transcriptional profiling identified that genes regulated by NF-ĸB, such as interleukin (IL)-12p40, were differentially modulated by the different type I strains. We subsequently showed that this difference in NF-ĸB activation was due to polymorphisms in GRA15. Furthermore, we observed that RH, but not other type I strains, recruited phosphorylated IĸBα (a component of the NF-ĸB complex) to the parasitophorous vacuole membrane and this recruitment of p- IĸBα was partially dependent on GRA2. We identified candidate parasite genes that could be responsible for phenotypic variation among the type I strains through comparative genomics and transcriptomics. We also identified differentially modulated host pathways among the type I strains, and these can serve as a guideline for future studies in examining the phenotypic differences among type I strains.


Acute complications of spinal cord injuries.
The aim of this paper is to give an overview of acute complications of spinal cord injury (SCI). Along with motor and sensory deficits, instabilities of the cardiovascular, thermoregulatory and broncho-pulmonary system are common after a SCI. Disturbances of the urinary and gastrointestinal systems are typical as well as sexual dysfunction. Frequent complications of cervical and high thoracic SCI are neurogenic shock, bradyarrhythmias, hypotension, ectopic beats, abnormal temperature control and disturbance of sweating, vasodilatation and autonomic dysreflexia. Autonomic dysreflexia is an abrupt, uncontrolled sympathetic response, elicited by stimuli below the level of injury. The symptoms may be mild like skin rash or slight headache, but can cause severe hypertension, cerebral haemorrhage and death. All personnel caring for the patient should be able to recognize the symptoms and be able to intervene promptly. Disturbance of respiratory function are frequent in tetraplegia and a primary cause of both short and long-term morbidity and mortality is pulmonary complications. Due to physical inactivity and altered haemostasis, patients with SCI have a higher risk of venous thromboembolism and pressure ulcers. Spasticity and pain are frequent complications which need to be addressed. The psychological stress associated with SCI may lead to anxiety and depression. Knowledge of possible complications during the acute phase is important because they may be life threatening and/ or may lead to prolonged rehabilitation.


Practitioner Review: Anxiety disorders in children and young people - assessment and treatment.
Despite significant advancements in our knowledge of anxiety disorders in children and adolescents, they continue to be underrecognised and undertreated. It is critical that these disorders are taken seriously in children and young people as they are highly prevalent, have a negative impact on educational, social and health functioning, create a risk of ongoing anxiety and other mental health disorders across the life span and are associated with substantial economic burden. Yet very few children with anxiety disorders access evidence-based treatments, and there is an urgent need for widespread implementation of effective interventions. This review aimed to provide an overview of recent research developments that will be relevant to clinicians and policymakers, particularly focusing on the development and maintenance of child anxiety disorders and considerations for assessment and treatment. Given the critical need to increase access to effective support, we hope this review will contribute to driving forward a step change in treatment delivery for children and young people with anxiety disorders and their families.


Structural and functional studies of the Pseudomonas aeruginosa minor pilin, PilE.
Many bacterial pathogens, including Pseudomonas aeruginosa, use type IVa pili (T4aP) for attachment and twitching motility. T4aP are composed primarily of major pilin subunits, which are repeatedly assembled and disassembled to mediate function. A group of pilin-like proteins, the minor pilins FimU and PilVWXE, prime pilus assembly and are incorporated into the pilus. We showed previously that minor pilin PilE depends on the putative priming subcomplex PilVWX and the non-pilin protein PilY1 for incorporation into pili, and that with FimU, PilE may couple the priming subcomplex to the major pilin PilA, allowing for efficient pilus assembly. Here we provide further support for this model, showing interaction of PilE with other minor pilins and the major pilin. A 1.25 Å crystal structure of PilEΔ1-28 shows a typical type IV pilin fold, demonstrating how it may be incorporated into the pilus. Despite limited sequence identity, PilE is structurally similar to Neisseria meningitidis minor pilins PilXNm and PilVNm, recently suggested via characterization of mCherry fusions to modulate pilus assembly from within the periplasm. A P. aeruginosa PilE-mCherry fusion failed to complement twitching motility or piliation of a pilE mutant. However, in a retraction-deficient strain where surface piliation depends solely on PilE, the fusion construct restored some surface piliation. PilE-mCherry was present in sheared surface fractions, suggesting that it was incorporated into pili. Together, these data provide evidence that PilE, the sole P. aeruginosa equivalent of PilXNm and PilVNm, likely connects a priming subcomplex to the major pilin, promoting efficient assembly of T4aP.


Warburg Effect - a Consequence or the Cause of Carcinogenesis?
Ever since its discovery (1924) the Warburg effect (aerobic glycolysis) remains an unresolved puzzle: why the aggressive cancer cells "prefer" to use the energetically highly inefficient method of burning the glucose at the cellular level? While in the course of the last 90 years several hypotheses have been suggested, to this date there is no clear explanation of this rather unusual effect. Even though it is commonly assumed that Warburg effect is a consequence of carcinogenesis, yet another hypothesis could be brought up that the cellular switch to aerobic glycolysis may represent the very point in time when a normal cell becomes cancerous. Furthermore, this switch may happen at the point where the fate of pyruvic acid is determined, caused by the inadequate supply of enzymes that promote citric as opposed to lactic acid cycle. Currently, few clinical observations, like low cancer incidence in Type 1 diabetes mellitus and increased cancer incidence in people on high carbohydrate diets might be called upon to support such hypothesis.


BOTDA measurements tolerant to non-local effects by using a phase-modulated probe wave and RF demodulation.
We demonstrate a Brillouin optical time domain analysis sensor based on a phase-modulated probe wave and RF demodulation that provides measurements tolerant to frequency-dependent variations of the pump pulse power induced by non-local effects. The tolerance to non-local effects is based on the special characteristics of the detection process, which provides an RF phase-shift signal that is largely independent of the Brillouin gain magnitude. Proof-of-concept experiments performed over a 20-km-long fiber demonstrate that the measured RF phase-shift spectrum remains unaltered for large frequency-dependent deformations of the pump pulse power. Therefore, it allows the use of a higher optical power of the probe wave, which leads to an enhancement of the detected signal to noise ratio. This can be used to extend the sensing distance, to improve the accuracy of the Brillouin frequency shift measurements, and to reduce the measurement time.


Cortical networks for control of voluntary arm movements under variable force conditions.
A neural model of voluntary movement and proprioception is developed that offers an integrated interpretation of the functional roles of diverse cell types in movement-related areas of primate cortex. The model circuit maintains accurate proprioception while controlling voluntary reaches to spatial targets, exertion of force against obstacles, posture maintenance despite perturbations, compliance with an imposed movement, and static and inertial load compensations. Computer simulations show that properties of model elements correspond to the properties of many known cells types in areas 4 and 5. Among these properties are delay period activation, response profiles during movement, kinematic and kinetic sensitivities, and latency of activity onset. In particular, area 4 phasic and tonic cells, respectively, compute velocity and position commands that are capable of activating alpha and gamma motor neurons, thereby shifting the mechanical equilibrium point. Anterior area 5 cells compute the position of the limb using corollary discharges from area 4 and feedback from muscle spindles. Posterior area 5 neurons use the position perception signal and a target position signal to compute a desired movement vector. The cortical loop is closed by a volition-gated projection of this movement vector to the area 4 phasic cells. An auxiliary circuit allows phasic-tonic cells in area 4 to incorporate force command components needed to compensate for static and inertial loads. After reporting simulations of prior experimental results, predictions are made for both motor and parietal cell types under novel experimental protocols.


Estradiol reverses excitatory synapse loss in a cellular model of neuropsychiatric disorders.
Loss of glutamatergic synapses is thought to be a key cellular pathology associated with neuropsychiatric disorders including schizophrenia (SCZ) and major depressive disorder (MDD). Genetic and cellular studies of SCZ and MDD using in vivo and in vitro systems have supported a key role for dysfunction of excitatory synapses in the pathophysiology of these disorders. Recent clinical studies have demonstrated that the estrogen, 17β-estradiol can ameliorate many of the symptoms experienced by patients. Yet, to date, our understanding of how 17β-estradiol exerted these beneficial effects is limited. In this study, we have tested the hypothesis that 17β-estradiol can restore dendritic spine number in a cellular model that recapitulates the loss of synapses associated with SCZ and MDD. Ectopic expression of wildtype, mutant or shRNA-mediated knockdown of Disrupted in Schizophrenia 1 (DISC1) reduced dendritic spine density in primary cortical neurons. Acute or chronic treatment with 17β-estradiol increased spine density to control levels in neurons with altered DISC1 levels. In addition, 17β-estradiol reduced the extent to which ectopic wildtype and mutant DISC1 aggregated. Furthermore, 17β-estradiol also caused the enrichment of synaptic proteins at synapses and increased the number of dendritic spines containing PSD-95 or that overlapped with the pre-synaptic marker bassoon. Taken together, our data indicates that estrogens can restore lost excitatory synapses caused by altered DISC1 expression, potentially through the trafficking of DISC1 and its interacting partners. These data highlight the possibility that estrogens exert their beneficial effects in SCZ and MDD in part by modulating dendritic spine number.


Attitudes and preferences on the use of mobile health technology and health games for self-management: interviews with older adults on anticoagulation therapy.
Older adults are at substantial risk for cardiovascular disorders that may require anticoagulation therapy. Those on warfarin therapy report dissatisfaction and reduced quality of life (QOL) resulting from the treatment. Advances in the area of mobile health (mHealth) technology have resulted in the design and development of new patient-centric models for the provision of personalized health care services to improve care delivery. However, there is a paucity of research examining the effectiveness of mHealth tools on knowledge, attitudes, and patient satisfaction with treatment, as well as self-management, adherence to therapy, and QOL in older adults with chronic illness conditions requiring long-term warfarin therapy. The objective of the study was to explore the attitudes and preferences of older adults on warfarin therapy regarding the use of mHealth technology and health games to gain skills for self-management. We conducted group and individual interviews with patients (60 years or older) on warfarin therapy at two anticoagulation clinics affiliated with an academic medical center. We held 4 group and 2 individual interviews, resulting in 11 patient participants and 2 family caregiver participants. We used structured questions on three topic areas including medication self-management strategies, mHealth technology use, and health games for exercise. We demonstrated some commercial health apps related to medication management, vitamin K content of food, and a videogame for balance exercise. Discussions were audiotaped and transcribed verbatim. Common themes were drawn using content analysis. The participants reported awareness of the importance of staying on schedule with warfarin therapy. They also acknowledged that negative experiences of friends or family members who were taking warfarin influenced their desire to keep on schedule with warfarin therapy. In addition, the participants expressed that the use of mHealth technology may be helpful for medication management. They also expressed the need for family support in the use of health technology devices. Moreover, the participants discussed concerns and challenges to use health technology and health games, and provided suggestions on ways to make mHealth technology and health games elder-friendly. These findings indicate that our older adults on warfarin therapy are interested in mHealth technology specific to warfarin medication management and health games. Further research needs to be done to validate these findings. Elder-friendly designs, technology support, and physical safety using mHealth technology may be useful in this population. These findings can be used to inform a larger study to design and test an elder-centered mHealth technology in this target population.


Epidemiology of palpable goiter in greater Buenos Aires, an iodine-sufficient area [corrected].
The Hospital de Clínicas organized a free program of goiter detection by palpation. This campaign was aimed at the population of the metropolitan area of Greater Buenos Aires (11 million inhabitants), with the prerequisite that each participant should be quite unaware whether he/she was a carrier of any thyroid disease. Attendees were split into two groups, i.e., Random and Induced. The former consisted of 542 individuals who came to consultation due to mere curiosity, while the latter involved 500 subjects, comprising consanguineous family members of patients with thyroid disorders and also individuals who suffered from other ailments. Ages ranged from 2 to 85 years. In the Random Group, goiter prevalence of 8.7% was observed, while in the Induced Group it climbed to 14.4%. Since both groups were mostly made up of women (87.2%), a correction based on the masculinity index was applied to members of the Random Group. Thus, the total observed prevalence of goiter was 6%, diffuse goiters corresponding to 3.5% and nodular ones to 2.5%. The frequency of nodules increased with age, 90.5% occurring in those over 40 years. In the Induced Group, goiter prevalence among relatives of patients with thyroid disorders proved to be 13.1%, rising to 17.8% in those who suffered from other complaints. The epidemic data presented herein are the first arising from a screening survey carried out in a large iodine-sufficient population of the southernmost tip of the American continent. These results are useful to build up the world map of goiter prevalence in non-endemic areas.


Vesicular glutamate transporter expression level affects synaptic vesicle release probability at hippocampal synapses in culture.
The vesicular glutamate transporter (VGLUT) plays an essential role in synaptic transmission by filling vesicles with glutamate. At mammalian synapses, VGLUT expression level determines the amount of glutamate packaged into vesicles, and the specific paralog of VGLUT expressed affects the release probability. In this study, we investigate whether there is a link between the number of VGLUTs on vesicles and release probability. We used a combination of electrophysiology and imaging techniques in cultured mouse hippocampal neurons where the VGLUT expression level has been severely altered. We found that vesicles with drastically reduced VGLUT expression were released with a lower probability. This deficit in release could only be rescued by a functional transporter, suggesting that the transport function, and not the molecular interactions, of the protein affects vesicle release. Based on these data, we propose a novel means of presynaptic vesicle release regulation--the intravesicular glutamate fill state of the vesicle.


Direct interaction in T-cells between thetaPKC and the tyrosine kinase p59fyn.
The protein kinase C (PKC) family has been clearly implicated in T-cell activation as have several nonreceptor protein-tyrosine kinases associated with the T-cell receptor, including p59fyn. This report demonstrates that thetaPKC and p59fyn specifically interact in vitro, in the yeast two-hybrid system, and in T-cells. Further indications of direct interaction are that p59fyn potentiates thetaPKC catalytic activity and that thetaPKC is a substrate for tyrosine phosphorylation by p59fyn. This interaction may account for the localization of thetaPKC following T-cell activation, pharmacological disruption of which results in specific cell-signaling defects. The demonstration of a physical interaction between a PKC and a protein-tyrosine kinase expands the class of PKC-anchoring proteins (receptors for activated C kinases (RACKs)) and demonstrates a direct connection between these two major T-cell-signaling pathways.


European lipodystrophy registry: background and structure.
Lipodystrophy syndromes comprise a group of extremely rare and heterogeneous diseases characterized by a selective loss of adipose tissue in the absence of nutritional deprivation or catabolic state. Because of the rarity of each lipodystrophy subform, research in this area is difficult and international co-operation mandatory. Therefore, in 2016, the European Consortium of Lipodystrophies (ECLip) decided to create a registry for patients with lipodystrophy. The registry was build using the information technology Open Source Registry System for Rare Diseases in the EU (OSSE), an open-source software and toolbox. Lipodystrophy specific data forms were developed based on current knowledge of typical signs and symptoms of lipodystrophy. The platform complies with the new General Data Protection Regulation (EU) 2016/679 by ensuring patient pseudonymization, informational separation of powers, secure data storage and security of communication, user authentication, person specific access to data, and recording of access granted to any data. Inclusion criteria are all patients with any form of lipodystrophy (with the exception of HIV-associated lipodystrophy). So far 246 patients from nine centres (Amsterdam, Bologna, Izmir, Leipzig, Münster, Moscow, Pisa, Santiago de Compostela, Ulm) have been recruited. With the help from the six centres on the brink of recruitment (Cambridge, Lille, Nicosia, Paris, Porto, Rome) this number is expected to double within the next one or 2 years. A European registry for all patients with lipodystrophy will provide a platform for improved research in the area of lipodystrophy. All physicians from Europe and neighbouring countries caring for patients with lipodystrophy are invited to participate in the ECLip Registry. ClinicalTrials.gov (NCT03553420). Registered 14 March 2018, retrospectively registered.


'Cosmetic boob jobs' or evidence-based breast surgery: an interpretive policy analysis of the rationing of 'low value' treatments in the English National Health Service.
In England the National Health Service (NHS) is not allowed to impose 'blanket bans' on treatments, but local commissioners produce lists of 'low value' procedures that they will normally not fund. Breast surgery is one example. However, evidence suggests that some breast surgery is clinically effective, with significant health gain. National guidelines indicate the circumstances under which breast surgery should be made available on the NHS, but there is widespread variation in their implementation.The purpose of this study was to explore the work practices of 'individual funding request' (IFR) panels, as they considered 'one-off' funding requests for breast surgery; examine how the notion of 'value' is dialogically constructed, and how decisions about who is deserving of NHS funding and who is not are accomplished in practice. We undertook ethnographic exploration of three IFR panels. We extracted all (22) breast surgery cases considered by these panels from our data set and progressively focused on three case discussions, one from each panel, covering the three main breast procedures.We undertook a microanalysis of the talk and texts arising from these cases, within a conceptual framework of interpretive policy analysis. Through an exploration of the symbolic artefacts (language, objects and acts) that are significant carriers of policy meaning, we identified the ways in which IFR panels create their own 'interpretive communities', within which deliberations about the funding of breast surgery are differently framed, and local decisions come to be justified. In particular, we demonstrated how each decision was contingent on [a] the evaluative accent given to certain words, [b] the work that documentary objects achieve in foregrounding particular concerns, and [c] the act of categorising. Meaning was constructed dialogically through local interaction and broader socio-cultural discourses about breasts and 'cosmetic' surgery. Despite the appeal of calls to tackle 'unwarranted variation' in access to low priority treatments by ensuring uniformity of local guidelines and policies, our findings suggest that ultimately, given the contingent nature of practice, this is likely to remain an illusory policy goal. Our findings challenge the scientistic thinking underpinning mainstream health policy discourse.


Chromosome replication in cell-free systems from Xenopus eggs.
Cell-free systems from eggs of the frog Xenopus laevis are able to perform most of the acts of eukaryotic chromosome replication in vitro. This now includes the crucial regulatory step of initiation, which had only been achieved for viral systems previously. Purified DNA or nuclei are able to initiate and complete semi-conservation replication in egg extracts in vitro (Blow & Laskey, Cell 47, 557-587 (1986). Replication does not require specialized DNA sequences either in vitro or in microinjected eggs, but in both systems large templates replicate more efficiently than small templates. In some cases replication can re-initiate, excluding the possibility that replication is primed by preexisting primers in the template preparations. When nuclei are replicated in vitro, only one round of replication is observed in a single incubation resembling the single round of replication observed for purified DNA after micro-injection. The mechanism that prevents re-initiation of replication within a single cell cycle is discussed and certain models are eliminated. Nucleosome assembly from histones and DNA has also been studied in cell-free systems from Xenopus eggs. Fractionation has led to the identification of two acidic proteins called nucleoplasmin and N1, which bind histones and transfer them to DNA. The sequences of both proteins have been determined by cDNA cloning and sequencing. Both proteins are found as complexes with histones in eggs.


A Metabolic Pathway for Activation of Dietary Glucosinolates by a Human Gut Symbiont.
Consumption of glucosinolates, pro-drug-like metabolites abundant in Brassica vegetables, has been associated with decreased risk of certain cancers. Gut microbiota have the ability to metabolize glucosinolates, generating chemopreventive isothiocyanates. Here, we identify a genetic and biochemical basis for activation of glucosinolates to isothiocyanates by Bacteroides thetaiotaomicron, a prominent gut commensal species. Using a genome-wide transposon insertion screen, we identified an operon required for glucosinolate metabolism in B. thetaiotaomicron. Expression of BT2159-BT2156 in a non-metabolizing relative, Bacteroides fragilis, resulted in gain of glucosinolate metabolism. We show that isothiocyanate formation requires the action of BT2158 and either BT2156 or BT2157 in vitro. Monocolonization of mice with mutant BtΔ2157 showed reduced isothiocyanate production in the gastrointestinal tract. These data provide insight into the mechanisms by which a common gut bacterium processes an important dietary nutrient.


Regional brain atrophy and functional disconnection across Alzheimer's disease evolution.
To assess the contribution of regional grey matter (GM) atrophy and functional disconnection in determining the level of cognitive decline in patients with Alzheimer's disease (AD) at different clinical stages. Ten patients with amnesic mild cognitive impairment (a-MCI), 11 patients with probable AD and 10 healthy controls were recruited. T1 volumes were obtained from each subject and postprocessed according to an optimised voxel based morphometry protocol. Resting state functional MRI data were also collected from the same individuals and analysed to produce connectivity maps after identification of the default mode network (DMN) by independent component analysis. Compared with healthy controls, both AD and a-MCI patients showed a similar regional pattern of brain disconnection between the posterior cingulate cortex (PCC) and the medial prefrontal cortex and the rest of the brain. Conversely, the distribution of GM atrophy was significantly more restricted in a-MCI than in AD patients. Interestingly, the PCC showed reduced connectivity in a-MCI patients in the absence of GM atrophy, which was, in contrast, detectable at the stage of fully developed AD. This study indicates that disconnection precedes GM atrophy in the PCC, which is a critical area of the DMN, and supports the hypothesis that GM atrophy in specific regions of AD brains likely reflects a long term effect of brain disconnection. In this context, our study indicates that GM atrophy in PCC accompanies the conversion from MCI to AD.


Acute Subjective and Behavioral Effects of Microdoses of Lysergic Acid Diethylamide in Healthy Human Volunteers.
Numerous anecdotal reports suggest that repeated use of very low doses of lysergic acid diethylamide (LSD), known as microdosing, improves mood and cognitive function. These effects are consistent both with the known actions of LSD on serotonin receptors and with limited evidence that higher doses of LSD (100-200 μg) positively bias emotion processing. Yet, the effects of such subthreshold doses of LSD have not been tested in a controlled laboratory setting. As a first step, we examined the effects of single very low doses of LSD (0-26 μg) on mood and behavior in healthy volunteers under double-blind conditions. Healthy young adults (N = 20) attended 4 laboratory sessions during which they received 0 (placebo), 6.5, 13, or 26 μg of LSD in randomized order at 1-week intervals. During expected peak drug effect, they completed mood questionnaires and behavioral tasks assessing emotion processing and cognition. Cardiovascular measures and body temperature were also assessed. LSD produced dose-related subjective effects across the 3 doses (6.5, 13, and 26 μg). At the highest dose, the drug also increased ratings of vigor and slightly decreased positivity ratings of images with positive emotional content. Other mood measures, cognition, and physiological measures were unaffected. Single microdoses of LSD produced orderly dose-related subjective effects in healthy volunteers. These findings indicate that a threshold dose of 13 μg of LSD might be used safely in an investigation of repeated administrations. It remains to be determined whether the drug improves mood or cognition in individuals with symptoms of depression.


Relative reactivity of biogenic and chemogenic uraninite and biogenic noncrystalline U(IV).
Aqueous chemical extractions and X-ray absorption spectroscopy (XAS) analyses were conducted to investigate the reactivity of chemogenic uraninite, nanoparticulate biogenic uraninite, and biogenic monomeric U(IV) species. The analyses were conducted in systems containing a total U concentration that ranged from 1.48 to 2.10 mM. Less than 0.02% of the total U was released to solution in extractions that targeted water-soluble and ion exchangeable fractions. Less than 5% of the total U was solubilized via complexation with a 0.1 M solution of NaF. Greater than 90% of the total U was extracted from biogenic uraninite and monomeric U(IV) after 6 h of reaction in an oxidizing solution of 50 mM K2S2O8. Additional oxidation experiments with lower concentrations (2 mM and 10 mM) of K2S2O8 and 8.2 mg L(-1) dissolved oxygen suggested that monomeric U(IV) species are more labile than biogenic uraninite; chemogenic uraninite was much less susceptible to oxidation than either form of biogenic U(IV). These results suggest that noncrystalline forms of U(IV) may be more labile than uraninite in subsurface environments. This work helps fill critical gaps in our understanding of the behavior of solid-associated U(IV) species in bioremediated sites and natural uranium ore deposits.


Construction of a virulent, green fluorescent protein-tagged Yersinia ruckeri and detection in trout tissues after intraperitoneal and immersion challenge.
A green fluorescent protein (GFP) expressing strain of Yersinia ruckeri was created by the transposition of a Tn10-GFP-kan cassette into the genome of Y. ruckeri Strain YRNC10. The derivative, YRNC10-gfp, was highly GFP fluorescent, retained the gfp-km marker in the absence of kanamycin selection, and exhibited in vitro growth kinetics similar to those of the wild type strain. YRNC10-gfp colonized and caused mortality in immersion and intraperitoneally challenged rainbow trout Oncorhynchus mykiss, although it was modestly attenuated compared to the wild type strain. The distribution and location of YRNC10-gfp in infected fish was visualized by epifluorescence microscopy. Abundant extracellular bacteria and a small number of intracellular bacteria were observed in the kidney, spleen and peripheral blood. To determine the percentage of trout cells containing intracellular bacteria, GFP fluorescence was measured by flow cytometry. A small population of GFP positive leukocytes was detected in peripheral blood (1.6%), spleen (1.1%) and anterior kidney (0.4%) tissues. In summary, this is the first report of the construction of a virulent, GFP-tagged Y. ruckeri, which may be a useful model for detecting and imaging the interactions between an aquatic pathogen and the natural salmonid host.


Large human outbreak of West Nile virus infection in north-eastern Italy in 2012.
Human cases of West Nile virus (WNV) disease have been reported in Italy since 2008. So far, most cases have been identified in north-eastern Italy, where, in 2012, the largest outbreak of WNV infection ever recorded in Italy occurred. Most cases of the 2012 outbreak were identified in the Veneto region, where a special surveillance plan for West Nile fever was in place. In this outbreak, 25 cases of West Nile neuroinvasive disease and 17 cases of fever were confirmed. In addition, 14 WNV RNA-positive blood donors were identified by screening of blood and organ donations and two cases of asymptomatic infection were diagnosed by active surveillance of subjects at risk of WNV exposure. Two cases of death due to WNND were reported. Molecular testing demonstrated the presence of WNV lineage 1 in all WNV RNA-positive patients and, in 15 cases, infection by the novel Livenza strain was ascertained. Surveillance in other Italian regions notified one case of neuroinvasive disease in the south of Italy and two cases in Sardinia. Integrated surveillance for WNV infection remains a public health priority in Italy and vector control activities have been strengthened in areas of WNV circulation.


Meta-analysis of trials comparing postoperative recovery after anesthesia with sevoflurane or desflurane.
Results of published, randomized controlled trials comparing sevoflurane and desflurane were pooled to measure differences in times until patients obeyed commands, were extubated, were oriented, were discharged from the postanesthesia care unit (PACU), and were ready to be discharged to home, as well as the occurrence of postoperative nausea and vomiting (PONV). We reviewed all randomized clinical trials in MEDLINE through December 18, 2003, with a title or abstract containing the words sevoflurane and desflurane. Two reviewers independently extracted study data from papers that met inclusion criteria. Endpoints were pooled using random-effects meta-analysis. Twenty-two reports of 25 studies (3 reports each described 2 studies) met our inclusion criteria. A total of 746 patients received sevoflurane, and 752 received desflurane. Patients receiving desflurane recovered 1-2 minutes quicker in the operating room than patients receiving sevoflurane. They obeyed commands 1.7 minutes sooner (p < 0.001; 95% confidence interval [CI], 0.7-2.7 minutes), were extubated 1.3 minutes sooner (p = 0.003; 95% CI, 0.4-2.2 minutes), and were oriented 1.8 minutes sooner (p < 0.001; 95% CI, 0.7-2.9 minutes). No significant differences were detected in the phase I or II PACU recovery times or in the rate of PONV. Meta-analysis of studies in which the duration of anesthesia was up to 3.1 hours indicated that patients receiving either desflurane or sevoflurane did not have significant differences in PACU time or PONV frequency. Patients receiving desflurane followed commands, were extubated, and were oriented 1.0-1.2 minutes earlier than patients receiving sevoflurane.


Risk Knowledge in Relapsing Multiple Sclerosis (RIKNO 1.0)--Development of an Outcome Instrument for Educational Interventions.
Adequate risk knowledge of patients is a prerequisite for shared decision making but few attempts have been made to develop assessment tools. Multiple Sclerosis (MS) is a chronic inflammatory disease of young adults with an increasing number of partially effective immunotherapies and therefore a paradigmatic disease to study patient involvement. Based on an item bank of MS risk knowledge items and patient feedback including perceived relevance we developed a risk knowledge questionnaire for relapsing remitting (RR) MS (RIKNO 1.0) which was a primary outcome measure in a patient education trial (192 early RRMS patients). Fourteen of the RIKNO 1.0 multiple-choice items were selected based on patient perceived relevance and item difficulty indices, and five on expert opinion. Mean item difficulty was 0.58, ranging from 0.14 to 0.79. Mean RIKNO 1.0 score increased after the educational intervention from 10.6 to 12.4 (p = 0.0003). Selected items were particularly difficult (e.g. those on absolute risk reductions of having a second relapse) and were answered correctly in only 30% of the patients, even after the intervention. Despite its high difficulty, RIKNO 1.0 is a responsive instrument to assess risk knowledge in RRMS patients participating in educational interventions.