Pulmonary vasoconstrictor action of KCNQ potassium channel blockers

KCNQ channels have been widely studied in the nervous system, heart and inner ear, where they have important physiological functions. Recent reports indicate that KCNQ channels may also be expressed in portal vein where they are suggested to influence spontaneous contractile activity. The biophysical properties of K+ currents mediated by KCNQ channels resemble a current underlying the resting K+ conductance and resting potential of pulmonary artery smooth muscle cells. We therefore investigated a possible role of KCNQ channels in regulating the function of pulmonary arteries by determining the ability of the selective KCNQ channel blockers, linopirdine and XE991, to promote pulmonary vasoconstriction. Linopirdine and XE991 both contracted rat and mouse pulmonary arteries but had little effect on mesenteric arteries. In each case the maximum contraction was almost as large as the response to 50 mM K+. Linopirdine had an EC50 of around 1 μM and XE991 was almost 10-fold more potent. Neither removal of the endothelium nor exposure to phentolamine or α,β-methylene ATP, to block α1-adrenoceptors or P2X receptors, respectively, affected the contraction. Contraction was abolished in Ca2+-free solution and in the presence of 1 μM nifedipine or 10 μM levcromakalim

New directions in cellular therapy of cancer: a summary of the summit on cellular therapy for cancer

A summit on cellular therapy for cancer discussed and presented advances related to the use of adoptive cellular therapy for melanoma and other cancers. The summit revealed that this field is advancing rapidly. Conventional cellular therapies, such as tumor infiltrating lymphocytes (TIL), are becoming more effective and more available. Gene therapy is becoming an important tool in adoptive cell therapy. Lymphocytes are being engineered to express high affinity T cell receptors (TCRs), chimeric antibody-T cell receptors (CARs) and cytokines. T cell subsets with more naïve and stem cell-like characteristics have been shown in pre-clinical models to be more effective than unselected populations and it is now possible to reprogram T cells and to produce T cells with stem cell characteristics. In the future, combinations of adoptive transfer of T cells and specific vaccination against the cognate antigen can be envisaged to further enhance the effectiveness of these therapies

Thalamic inputs to dorsomedial striatum are involved in inhibitory control: evidence from the five-choice serial reaction time task in rats

Rationale Corticostriatal circuits are widely implicated in the top-down control of attention including inhibitory control and behavioural flexibility. However, recent neurophysiological evidence also suggests a role for thalamic inputs to striatum in behaviours related to salient, reward-paired cues. Objectives Here, we used designer receptors exclusively activated by designer drugs (DREADDs) to investigate the role of parafascicular (Pf) thalamic inputs to the dorsomedial striatum (DMS) using the five-choice serial reaction time task (5CSRTT) in rats. Methods The 5CSRTT requires sustained attention in order to detect spatially and temporally distributed visual cues and provides measures of inhibitory control related to impulsivity (premature responses) and compulsivity (perseverative responses). Rats underwent bilateral Pf injections of the DREADD vector, AAV2-CaMKIIa-HA-hM4D(Gi)-IRES-mCitrine. The DREADD agonist, clozapine N-oxide (CNO; 1 μl bilateral; 3 μM) or vehicle, was injected into DMS 1 h before behavioural testing. Task parameters were manipulated to increase attention load or reduce stimulus predictability respectively. Results We found that inhibition of the Pf-DMS projection significantly increased perseverative responses when stimulus predictability was reduced but had no effect on premature responses or response accuracy, even under increased attentional load. Control experiments showed no effects on locomotor activity in an open field. Conclusions These results complement previous lesion work in which the DMS and orbitofrontal cortex were similarly implicated in perseverative responses and suggest a specific role for thalamostriatal inputs in inhibitory control

Seagrass can mitigate negative ocean acidification effects on calcifying algae

The ultimate effect that ocean acidification (OA) and warming will have on the physiology of calcifying algae is still largely uncertain. Responses depend on the complex interactions between seawater chemistry, global/local stressors and species-specific physiologies. There is a significant gap regarding the effect that metabolic interactions between coexisting species may have on local seawater chemistry and the concurrent effect of OA. Here, we manipulated CO2 and temperature to evaluate the physiological responses of two common photoautotrophs from shallow tropical marine coastal ecosystems in Brazil: the calcifying alga Halimeda cuneata, and the seagrass Halodule wrightii. We tested whether or not seagrass presence can influence the calcification rate of a widespread and abundant species of Halimeda under OA and warming. Our results demonstrate that under elevated CO2, the high photosynthetic rates of H. wrightii contribute to raise H. cuneata calcification more than two-fold and thus we suggest that H. cuneata populations coexisting with H. wrightii may have a higher resilience to OA conditions. This conclusion supports the more general hypothesis that, in coastal and shallow reef environments, the metabolic interactions between calcifying and non-calcifying organisms are instrumental in providing refuge against OA effects and increasing the resilience of the more OA-susceptible species.E.B. would like to thank the Coordenação de Aperfeiçoamento de Pessoas de Nível Superior (CAPES) for Masters funding. Funding for this project came from the Synergism grant (CNPq 407365/2013-3). We extend our thanks to the Brazil-based Projeto Coral Vivo and its sponsor PetroBras Ambiental for providing the Marine Mesocosm structure and experimental assistance.info:eu-repo/semantics/publishedVersio

Characterisation of the pathogenic effects of the in vivo expression of an ALS-linked mutation in D-amino acid oxidase: Phenotype and loss of spinal cord motor neurons

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset neuromuscular disorder characterised by selective loss of motor neurons leading to fatal paralysis. Current therapeutic approaches are limited in their effectiveness. Substantial advances in understanding ALS disease mechanisms has come from the identification of pathogenic mutations in dominantly inherited familial ALS (FALS). We previously reported a coding mutation in D-amino acid oxidase (DAOR199W) associated with FALS. DAO metabolises D-serine, an essential co-agonist at the N-Methyl-D-aspartic acid glutamate receptor subtype (NMDAR). Using primary motor neuron cultures or motor neuron cell lines we demonstrated that expression of DAOR199W, promoted the formation of ubiquitinated protein aggregates, activated autophagy and increased apoptosis. The aim of this study was to characterise the effects of DAOR199W in vivo, using transgenic mice overexpressing DAOR199W. Marked abnormal motor features, e.g. kyphosis, were evident in mice expressing DAOR199W, which were associated with a significant loss (19%) of lumbar spinal cord motor neurons, analysed at 14 months. When separated by gender, this effect was greater in females (26%; p< 0.0132). In addition, we crossed the DAOR199W transgenic mouse line with the SOD1G93A mouse model of ALS to determine whether the effects of SOD1G93A were potentiated in the double transgenic line (DAOR199W/SOD1G93A). Although overall survival was not affected, onset of neurological signs was significantly earlier in female double transgenic animals than their female SOD1G93A littermates (125 days vs 131 days, P = 0.0239). In summary, some significant in vivo effects of DAOR199W on motor neuron function (i.e. kyphosis and loss of motor neurons) were detected which were most marked in females and could contribute to the earlier onset of neurological signs in double transgenic females compared to SOD1G93A littermates, highlighting the importance of recognizing gender effects present in animal models of ALS

Getting the right balance: insole design alters the static balance of people with diabetes and neuropathy

BACKGROUND: Over 1 in 3 older people with diabetes sustain a fall each year. Postural instability has been identified as independent risk factor for falls within people with Diabetic Peripheral Neuropathy (DPN). People with DPN, at increased risk of falls, are routinely required to wear offloading insoles, yet the impact of these insoles on postural stability and postural control is unknown. The aim of this study was to evaluate the effect of a standard offloading insole and its constituent parts on the balance in people with DPN. METHODS: A random sample of 50 patients with DPN were observed standing for 3 × 30 s, and stepping in response to a light, under five conditions presented in a random order; as defined by a computer program; 1) no insole, 2) standard diabetic: a standard offloading insole made from EVA/poron®, and three other insoles with one design component systematically altered 3) flat: diabetic offloading insole with arch fill removed, 4) low resilient memory: diabetic offloading insole with the cover substituted with low resilience memory V9, 5) textured: diabetic offloading insole with a textured PVC surface added (Algeos Ltd). After each condition participants self-rated perceived steadiness. RESULTS: Insole design effected static balance and balance perception, but not stepping reaction time in people with DPN. The diabetic and memory shaped insoles (with arch fill) significantly increased centre of pressure velocity (14 %, P = 0.006), (13 %, P = 0.001), and path length (14 %, P = 0.006), (13 %, P = 001), when compared to the no insole condition. The textured shaped and flat soft insole had no effect on static balance when compared to the no insole condition (P > 0.05). CONCLUSION: Insoles have an effect on static balance but not stepping reaction time. This effect is independent of neuropathy severity. The addition of a textured cover seems to counter the negative effect of an arch fill, even in participants with severe sensation loss. Static balance is unaffected by material softness or resilience. Current best practice of providing offloading insoles, with arch fill, to increase contact area and reduce peak pressure could be making people more unstable. Whilst flat, soft insoles maybe the preferable design option for those with poor balance. There is a need to develop an offloading insole that can reduce diabetic foot ulcer risk, without compromising balance

The holistic phase model of early adult crisis

The objective of the current study was to explore the structural, temporal and experiential manifestations of crisis episodes in early adulthood, using a holistic-systemic theoretical framework. Based on an analysis of 50 interviews with individuals about a crisis episode between the ages of 25 and 35, a holistic model was developed. The model comprises four phases: (1) Locked-in, (2) Separation/Time-out, (3) Exploration and (4) Rebuilding, which in turn have characteristic features at four levels—person-in-environment, identity, motivation and affect-cognition. A crisis starts out with a commitment at work or home that has been made but is no longer desired, and this is followed by an emotionally volatile period of change as that commitment is terminated. The positive trajectory of crisis involves movement through an exploratory period towards active rebuilding of a new commitment, but ‘fast-forward’ and ‘relapse’ loops can interrupt Phases 3 and 4 and make a positive resolution of the episode less likely. The model shows conceptual links with life stage theories of emerging adulthood and early adulthood, and it extends current understandings of the transitional developmental challenges that young adults encounter

Computer simulation of breast reduction surgery

Background: Plastic surgery of the breast, particularly breast reduction, is considered difficult. It can become a challenge for a less experienced surgeon to understand exactly what to do when facing a particular type of breast and how to avoid unsatisfactory results. Methods: The goal of this study was to create a computer model of the breast that provides a basis for the simulation of breast surgery, particularly breast reduction. The reconstruction of elastic parameters is based on observations of the breast with the patient in different positions. Results: It is shown that several measurements with the patient in different positions allow one to choose the parameters of the model and determine the elastic coefficients of the breast and the skin. The geometry of the breast before and after surgery is simulated. A qualitative study of the incision parameters’ influence on the final geometry of the breast is presented. Conclusion: The developed methodology and software allow one to estimate the form of the breast after the surgery by knowing its form before surgery and taking into consideration the parameters of incision applied by the surgeon at the time of surgery. The described approach can be used for the qualitative and quantitative study of breast reduction surgery with a satisfactory result. Level of Evidence: V (This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266.

Role of Dopamine D2 Receptors in Human Reinforcement Learning

Influential neurocomputational models emphasize dopamine (DA) as an electrophysiological and neurochemical correlate of reinforcement learning. However, evidence of a specific causal role of DA receptors in learning has been less forthcoming, especially in humans. Here we combine, in a between-subjects design, administration of a high dose of the selective DA D2/3-receptor antagonist sulpiride with genetic analysis of the DA D2 receptor in a behavioral study of reinforcement learning in a sample of 78 healthy male volunteers. In contrast to predictions of prevailing models emphasizing DA's pivotal role in learning via prediction errors, we found that sulpiride did not disrupt learning, but rather induced profound impairments in choice performance. The disruption was selective for stimuli indicating reward, while loss avoidance performance was unaffected. Effects were driven by volunteers with higher serum levels of the drug, and in those with genetically-determined lower density of striatal DA D2 receptors. This is the clearest demonstration to date for a causal modulatory role of the DA D2 receptor in choice performance that might be distinct from learning. Our findings challenge current reward prediction error models of reinforcement learning, and suggest that classical animal models emphasizing a role of postsynaptic DA D2 receptors in motivational aspects of reinforcement learning may apply to humans as well.Neuropsychopharmacology accepted article peview online, 09 April 2014; doi:10.1038/npp.2014.84

Effects of dopamine D2/D3 receptor antagonism on human planning and spatial working memory

Psychopharmacological studies in humans suggest important roles for dopamine (DA) D2 receptors in human executive functions, such as cognitive planning and spatial working memory (SWM). However, studies that investigate an impairment of such functions using the selective DA D2/3 receptor antagonist sulpiride have yielded inconsistent results, perhaps because relatively low doses were used. We believe we report for the first time, the effects of a higher (800 mg p.o.) single dose of sulpiride as well as of genetic variation in the DA receptor D2 gene (DA receptor D2 Taq1A polymorphism), on planning and working memory. With 78 healthy male volunteers, we apply a between-groups, placebo-controlled design. We measure outcomes in the difficult versions of the Cambridge Neuropsychological Test Automated Battery One-Touch Stockings of Cambridge and the self-ordered SWM task. Volunteers in the sulpiride group showed significant impairments in planning accuracy and, for the more difficult problems, in SWM. Sulpiride administration speeded response latencies in the planning task on the most difficult problems. Volunteers with at least one copy of the minor allele (A1+) of the DA receptor D2 Taq1A polymorphism showed better SWM capacity, regardless of whether they received sulpiride or placebo. There were no effects on blood pressure, heart rate or subjective sedation. In sum, a higher single dose of sulpiride impairs SWM and executive planning functions, in a manner independent of the DA receptor D2 Taq1A polymorphism.This research work was funded by a Core Award from the Medical Research Council and the Wellcome Trust to the Behavioural and Clinical Neuroscience Institute (MRC Ref G1000183; WT Ref 093875/Z/10/Z). Also supported by a Wellcome Trust Senior Investigator Award (104631/Z/14/Z) awarded to TWR. CE was supported by the Swiss National Science Foundation (PA00P1_134135) and the Vienna Science and Technology Fund (WWTF VRG13-007)