Kv7 Channels in Cyclic-Nucleotide Dependent Relaxation of Rat Intra-Pulmonary Artery

Pulmonary hypertension is treated with drugs that stimulate cGMP or cAMP signalling. Both nucleotides can activate Kv7 channels, leading to smooth muscle hyperpolarisation, reduced Ca(2+) influx and relaxation. Kv7 activation by cGMP contributes to the pulmonary vasodilator action of nitric oxide, but its contribution when dilation is evoked by the atrial natriuretic peptide (ANP) sensitive guanylate cyclase, or cAMP, is unknown. Small vessel myography was used to investigate the ability of Kv7 channel blockers to interfere with pulmonary artery relaxation when cyclic nucleotide pathways were stimulated in different ways. The pan-Kv7 blockers, linopirdine and XE991, caused substantial inhibition of relaxation evoked by NO donors and ANP, as well as endothelium-dependent dilators, the guanylate cyclase stimulator, riociguat, and the phosphodiesterase-5 inhibitor, sildenafil. Maximum relaxation was reduced without a change in sensitivity. The blockers had relatively little effect on cAMP-mediated relaxation evoked by forskolin, isoprenaline or treprostinil. The Kv7.1-selective blocker, HMR1556, had no effect on cGMP or cAMP-dependent relaxation. Western blot analysis demonstrated the presence of Kv7.1 and Kv7.4 proteins, while selective activators of Kv7.1 and Kv7.4 homomeric channels, but not Kv7.5, caused pulmonary artery relaxation. It is concluded that Kv7.4 channels contribute to endothelium-dependent dilation and the effects of drugs that act by stimulating cGMP, but not cAMP, signalling

Novel sources of resistance to Striga hermonthica in Tripsacum dactyloides, a wild relative of maize

• The parasitic weed Striga hermonthica lowers cereal yield in small-holder farms in Africa. Complete resistance in maize to S. hermonthica infection has not been identified. A valuable source of resistance to S. hermonthica may lie in the genetic potential of wild germplasm.• The susceptibility of a wild relative of maize, Tripsacum dactyloides and a Zea mays–T. dactyloides hybrid to S. hermonthica infection was determined. Striga hermonthica development was arrested after attachment to T. dactyloides. Vascular continuity was established between parasite and host but there was poor primary haustorial tissue differentiation on T. dactyloides compared with Z. mays. Partial resistance was inherited in the hybrid.• Striga hermonthica attached to Z. mays was manipulated such that different secondary haustoria could attach to different hosts. Secondary haustoria formation was inhibited on T. dactyloides, moreover, subsequent haustoria formation on Z. mays was also impaired.• Results suggest that T. dactyloides produces a signal that inhibits haustorial development: this signal may be mobile within the parasite haustorial root syste

Dominant immunosuppression of dendritic cell function by prostate-cancer-derived exosomes

Exosomes are a distinct population of extracellular vesicles of endocytic origin with a protein repertoire similar to the parent cell. Although tumour-derived exosomes harbour immunosuppressive characteristics, they also carry tumour antigens and thus potentially contribute to immune activation. The aim of this study was to examine the impact of prostate cancer exosomes on tumour antigen cross-presentation. DU145 cells, transduced with shRNA to knockdown Rab27a (DU145KD) that inhibits exosome secretion, triggered significantly stronger tumour-antigen-specific T cell responses when loaded onto dendritic cells (DC) than control DU145 cells. Enhanced T cell response was prevented by adding purified exogenous DU145 exosomes to DU145KD cells, demonstrating that the dominant effect of tumour exosomes is immunosuppression and not antigen delivery. CD8+ T cell responses were impaired via exosomal regulation of DC function; exosomes triggered the expression of CD73, an ecto-5-nucleotidase responsible for AMP to adenosine hydrolysis, on DC. CD73 induction on DC that constitutively express CD39 resulted in an ATP-dependent inhibition of TNFα- and IL-12-production. We identified exosomal prostaglandin E2 (PGE2) as a potential driver of CD73 induction, as inhibition of PGE2 receptors significantly reduced exosome-dependent CD73 induction. The results reveal a hitherto unknown suppression of DC function via exosomal PGE2, adding a new element to tumour exosome–immune cell cross-talk

Obesity and metabolic syndrome in adolescent survivors of standard risk childhood acute lymphoblastic leukemia in Saudi Arabia

This study estimated prevalence of unhealthy weight status and metabolic syndrome (MS) amongst Saudi survivors of standard risk ALL. Procedure. We recruited 56 survivors, mean age 13.4 years (SD 4.1), a mean of 9.1 years (SD 4.1) postdiagnosis. The BMI for age was used to define weight status relative to national (Saudi) and international (Cole et al., Cole-IOTF, WHO, and CDC) reference data. We measured body composition by dualenergy X-ray absorptiometry (DXA), waist circumference, blood pressure, lipid profile (HDL-C, Triglycerides), fasting glucose and insulin. Results. According to international definitions based on BMI for age, around half of the sample had unhealthy weight status. All of the approaches based on BMI for age underestimated overfatness, present in 27/51 (53%) of the sample according to DXA. Prevalence of MS was 7.1% (3/42 of those over 9-years old) and 5.4% (3/56) by applying the International Diabetes Federation (IDF) definition and National Cholesterol Education Program Third Adult Treatment panel Guidelines (NCEP III), respectively. However, MS by the NCEP III definition was present in 19% of the overweight and obese survivors and 7.1% of the sample had at least two of the components of MS. Conclusion. Unhealthy body weight and overfatness may be common amongst adolescent Saudi survivors of standard risk ALL, though overweight and obesity may be no more common than in the general Saudi adolescent population. Defining weight status using BMI underestimates overfatness. Ideally, body composition and cardiometabolic risk factors should be monitored at late effects clinics. Pediatr Blood Cancer 2012;59: 133–137. 2011 Wiley Periodicals, Inc

Comparison of perinatal outcomes for all modes of second stage delivery in obstetric theatres : a retrospective observational study

Objective To compare rates of vaginal delivery and adverse outcomes of instrumental delivery trials in obstetric theatre compared to primary emergency full dilatation Caesarean section Design Retrospective cohort study Setting University teaching hospital Population Women with singleton, non-anomalous, pregnancy undergoing instrumental delivery trial in obstetric theatre Methods Data was collected from consecutive cases during 2014 until 2018 using clinical records. Multivariate regression analysis was used comparing groups per first delivery attempt. Main Outcome Measures Primary outcome was completion of vaginal delivery between all methods of instrumental delivery. Secondary outcome was a composite of immediate perinatal adverse outcomes for instrumental delivery modes and primary full dilatation Caesarean section. Results From 971 deliveries analysed: ventouse delivery was significantly less likely to achieve vaginal delivery compared to Keilland’s forceps delivery (OR 0.42, 95%CI 0.22-0.79). Once confounding factors were adjusted for, adverse outcome rates were less frequent in the Keilland’s forceps group compared with primary full dilatation Caesarean section (OR 0.37, 95% CI: 0.16-0.81), however the receiver operating characteristic curve produced from this model demonstrated low predictive value (AUC 0.64). Conclusions Attempting instrumental delivery in delivery suite theatre, as an alternative to primary emergency full dilatation Caesarean section, is both reasonable and safe. Ventouse delivery in this situation may be associated with a higher chance of failure than other modes of instrumental delivery, thus making appropriate choice of delivery method of paramount importance according to each clinical situation. Funding None Keywords Caesarean section, Keilland’s forceps, ventouse, trial of instrumental deliver

T helper cell subsets specific for pseudomonas aeruginosa in healthy individuals and patients with cystic fibrosis

Background: We set out to determine the magnitude of antigen-specific memory T helper cell responses to Pseudomonas aeruginosa in healthy humans and patients with cystic fibrosis. Methods: Peripheral blood human memory CD4+ T cells were co-cultured with dendritic cells that had been infected with different strains of Pseudomonas aeruginosa. The T helper response was determined by measuring proliferation, immunoassay of cytokine output, and immunostaining of intracellular cytokines. Results: Healthy individuals and patients with cystic fibrosis had robust antigen-specific memory CD4+ T cell responses to Pseudomonas aeruginosa that not only contained a Th1 and Th17 component but also Th22 cells. In contrast to previous descriptions of human Th22 cells, these Pseudomonal-specific Th22 cells lacked the skin homing markers CCR4 or CCR10, although were CCR6+. Healthy individuals and patients with cystic fibrosis had similar levels of Th22 cells, but the patient group had significantly fewer Th17 cells in peripheral blood. Conclusions: Th22 cells specific to Pseudomonas aeruginosa are induced in both healthy individuals and patients with cystic fibrosis. Along with Th17 cells, they may play an important role in the pulmonary response to this microbe in patients with cystic fibrosis and other conditions

Stage‐structured population systems with temporally periodic delay

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/115917/1/mma3424_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/115917/2/mma3424.pd

Network 'small-world-ness': a quantitative method for determining canonical network equivalence

Background: Many technological, biological, social, and information networks fall into the broad class of 'small-world' networks: they have tightly interconnected clusters of nodes, and a shortest mean path length that is similar to a matched random graph (same number of nodes and edges). This semi-quantitative definition leads to a categorical distinction ('small/not-small') rather than a quantitative, continuous grading of networks, and can lead to uncertainty about a network's small-world status. Moreover, systems described by small-world networks are often studied using an equivalent canonical network model-the Watts-Strogatz (WS) model. However, the process of establishing an equivalent WS model is imprecise and there is a pressing need to discover ways in which this equivalence may be quantified. Methodology/Principal Findings: We defined a precise measure of 'small-world-ness' S based on the trade off between high local clustering and short path length. A network is now deemed a 'small-world' if S. 1-an assertion which may be tested statistically. We then examined the behavior of S on a large data-set of real-world systems. We found that all these systems were linked by a linear relationship between their S values and the network size n. Moreover, we show a method for assigning a unique Watts-Strogatz (WS) model to any real-world network, and show analytically that the WS models associated with our sample of networks also show linearity between S and n. Linearity between S and n is not, however, inevitable, and neither is S maximal for an arbitrary network of given size. Linearity may, however, be explained by a common limiting growth process. Conclusions/Significance: We have shown how the notion of a small-world network may be quantified. Several key properties of the metric are described and the use of WS canonical models is placed on a more secure footing

The Mystique of Macro-Boycotting Behaviour: A Conceptual Framework

In spite of the aim of the World Trade Organization and other international organizations to foster international trade and development by lessening protectionism agendas worldwide, there has been a rise in consumer boycotting behaviour at a macro level involving campaigns directed against foreign products from countries embroiled in conflicts in international relations, rather than against products from individual companies perceived to have engaged in a domestic egregious act. While campaigning at this level is becoming a more effective tool for consumer protest, as it negatively affects both the boycotted countries’ macroeconomics and companies’ micro-competitiveness, consumer motivations to participate in macro-level boycotts has so far been overlooked in the boycotting literature. This paper examines consumers’ behavioural intentions to participate in macro-boycotting campaigns within the context of an Arab country, which has recently witnessed a number of campaigns of this nature. Using the theory of planned behaviour the findings of an exploratory qualitative study of Egyptian consumers offer insights into the motives and barriers to individual macro-boycott participation. Findings are discussed together with managerial implications

Changing pattern in the basal ganglia: motor switching under reduced dopaminergic drive

Action selection in the basal ganglia is often described within the framework of a standard model, associating low dopaminergic drive with motor suppression. Whilst powerful, this model does not explain several clinical and experimental data, including varying therapeutic efficacy across movement disorders. We tested the predictions of this model in patients with Parkinson’s disease, on and off subthalamic deep brain stimulation (DBS), focussing on adaptive sensory-motor responses to a changing environment and maintenance of an action until it is no longer suitable. Surprisingly, we observed prolonged perseverance under on-stimulation, and high inter-individual variability in terms of the motor selections performed when comparing the two conditions. To account for these data, we revised the standard model exploring its space of parameters and associated motor functions and found that, depending on effective connectivity between external and internal parts of the globus pallidus and saliency of the sensory input, a low dopaminergic drive can result in increased, dysfunctional, motor switching, besides motor suppression. This new framework provides insight into the biophysical mechanisms underlying DBS, allowing a description in terms of alteration of the signal-to-baseline ratio in the indirect pathway, which better account of known electrophysiological data in comparison with the standard model