Hormonal responses to cholinergic input are different in humans with and without type 2 diabetes mellitus

<div><p>Peripheral muscarinic acetylcholine receptors regulate insulin and glucagon release in rodents but their importance for similar roles in humans is unclear. Bethanechol, an acetylcholine analogue that does not cross the blood-brain barrier, was used to examine the role of peripheral muscarinic signaling on glucose homeostasis in humans with normal glucose tolerance (NGT; n = 10), impaired glucose tolerance (IGT; n = 11), and type 2 diabetes mellitus (T2DM; n = 9). Subjects received four liquid meal tolerance tests, each with a different dose of oral bethanechol (0, 50, 100, or 150 mg) given 60 min before a meal containing acetaminophen. Plasma pancreatic polypeptide (PP), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucose, glucagon, C-peptide, and acetaminophen concentrations were measured. Insulin secretion rates (ISRs) were calculated from C-peptide levels. Acetaminophen and PP concentrations were surrogate markers for gastric emptying and cholinergic input to islets. The 150 mg dose of bethanechol increased the PP response 2-fold only in the IGT group, amplified GLP-1 release in the IGT and T2DM groups, and augmented the GIP response only in the NGT group. However, bethanechol did not alter ISRs or plasma glucose, glucagon, or acetaminophen concentrations in any group. Prior studies showed infusion of xenin-25, an intestinal peptide, delays gastric emptying and reduces GLP-1 release but not ISRs when normalized to plasma glucose levels. Analysis of archived plasma samples from this study showed xenin-25 amplified postprandial PP responses ~4-fold in subjects with NGT, IGT, and T2DM. Thus, increasing postprandial cholinergic input to islets augments insulin secretion in mice but not humans.</p><p><b><i>Trial Registration</i>:</b> ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01434901?term=NCT01434901&rank=1" target="_blank">NCT01434901</a></p></div

Subjective health expectations of patients with age-related macular degeneration treated with antiVEGF drugs

BACKGROUND: Subjective expectations regarding future health may influence patients' judgement of current health and treatment effects, as well as adherence to therapies in chronic diseases. We aimed to explore subjective expectations on longevity and future health-related quality of life (HRQOL) of patients with age-related macular degeneration (AMD) treated with antiVEGF injections and analyse the influencing factors. METHODS: Consecutive AMD patients in two ophthalmology centres were included. Demographics, clinical characteristics and informal care utilisation were recorded. Current health was evaluated by the EQ-5D generic health status questionnaire and time trade-off (TTO) methods. Happiness was measured on a visual analogue scale (VAS). Subjective life-expectancy and expected EQ-5D status at ages 70, 80 and 90 were surveyed. T-test was applied to compare subgroups and Pearson correlations were performed to analyse relationships between variables. RESULTS: One hundred twenty two patients were involved (females 62%) with a mean (SD) age of 75.2 (7.9) years and disease duration of 2.9 (2.5) years. The majority were in AREDS-4 state, the better eye's ETDRS was 64.7 (15.4). EQ-5D and TTO revealed moderate deterioration of health (0.66 vs. 0.72, p = 0.131), happiness VAS was 6.3 (2.2). Correlation between EQ-5D and ETDRS was moderate (R = 0.242, p < 0.05) and having both versus one eye in AREDS-4 resulted lower TTO (0.68 vs. 0.83; p = 0.013). Subjective life-expectancy did not differ significantly from statistical life-expectancy and had no significant impact on TTO. The self-estimated mean EQ-5D score was 0.60, 0.40 and 0.24 for ages 70, 80 and 90 which is lower than the population norm of age-groups 65-74, 75-84 and 85+ (0.77, 0.63 and 0.63, respectively). Age, gender, current EQ-5D, need for informal care and happiness were deterministic factors of subjective health expectations. CONCLUSION: AMD patients with antiVEGF treatment have comparable HRQOL as the age-matched general public but expect a more severe deterioration of health with age. Older patients with worse HRQOL have worse subjective expectations. Exploring patients' health expectations provides an opportunity for ophthalmologists to correct misperceptions and improve the quality of AMD care. Further studies should provide evidences on the relationship between subjective expectations and actual health outcomes, and on its impact on patients' AMD-specific health behaviour

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Overview of progress in European medium sized tokamaks towards an integrated plasma-edge/wall solution

Integrating the plasma core performance with an edge and scrape-off layer (SOL) that leads to tolerable heat and particle loads on the wall is a major challenge. The new European medium size tokamak task force (EU-MST) coordinates research on ASDEX Upgrade (AUG), MAST and TCV. This multi-machine approach within EU-MST, covering a wide parameter range, is instrumental to progress in the field, as ITER and DEMO core/pedestal and SOL parameters are not achievable simultaneously in present day devices. A two prong approach is adopted. On the one hand, scenarios with tolerable transient heat and particle loads, including active edge localised mode (ELM) control are developed. On the other hand, divertor solutions including advanced magnetic configurations are studied. Considerable progress has been made on both approaches, in particular in the fields of: ELM control with resonant magnetic perturbations (RMP), small ELM regimes, detachment onset and control, as well as filamentary scrape-off-layer transport. For example full ELM suppression has now been achieved on AUG at low collisionality with n  =  2 RMP maintaining good confinement ${{H}_{\text{H}\left(98,\text{y}2\right)}}\approx 0.95$ . Advances have been made with respect to detachment onset and control. Studies in advanced divertor configurations (Snowflake, Super-X and X-point target divertor) shed new light on SOL physics. Cross field filamentary transport has been characterised in a wide parameter regime on AUG, MAST and TCV progressing the theoretical and experimental understanding crucial for predicting first wall loads in ITER and DEMO. Conditions in the SOL also play a crucial role for ELM stability and access to small ELM regimes

Progress from ASDEX Upgrade experiments in preparing the physics basis of ITER operation and DEMO scenario development

An overview of recent results obtained at the tokamak ASDEX Upgrade (AUG) is given. A work flow for predictive profile modelling of AUG discharges was established which is able to reproduce experimental H-mode plasma profiles based on engineering parameters only. In the plasma center, theoretical predictions on plasma current redistribution by a dynamo effect were confirmed experimentally. For core transport, the stabilizing effect of fast ion distributions on turbulent transport is shown to be important to explain the core isotope effect and improves the description of hollow low-Z impurity profiles. The L-H power threshold of hydrogen plasmas is not affected by small helium admixtures and it increases continuously from the deuterium to the hydrogen level when the hydrogen concentration is raised from 0 to 100%. One focus of recent campaigns was the search for a fusion relevant integrated plasma scenario without large edge localised modes (ELMs). Results from six different ELM-free confinement regimes are compared with respect to reactor relevance: ELM suppression by magnetic perturbation coils could be attributed to toroidally asymmetric turbulent fluctuations in the vicinity of the separatrix. Stable improved confinement mode plasma phases with a detached inner divertor were obtained using a feedback control of the plasma β. The enhanced D α H-mode regime was extended to higher heating power by feedback controlled radiative cooling with argon. The quasi-coherent exhaust regime was developed into an integrated scenario at high heating power and energy confinement, with a detached divertor and without large ELMs. Small ELMs close to the separatrix lead to peeling-ballooning stability and quasi continuous power exhaust. Helium beam density fluctuation measurements confirm that transport close to the separatrix is important to achieve the different ELM-free regimes. Based on separatrix plasma parameters and interchange-drift-Alfvén turbulence, an analytic model was derived that reproduces the experimentally found important operational boundaries of the density limit and between L- and H-mode confinement. Feedback control for the X-point radiator (XPR) position was established as an important element for divertor detachment control. Stable and detached ELM-free phases with H-mode confinement quality were obtained when the XPR was moved 10 cm above the X-point. Investigations of the plasma in the future flexible snow-flake divertor of AUG by means of first SOLPS-ITER simulations with drifts activated predict beneficial detachment properties and the activation of an additional strike point by the drifts

Real-time plasma state monitoring and supervisory control on TCV

In ITER and DEMO, various control objectives related to plasma control must be simultaneously achieved by the plasma control system (PCS), in both normal operation as well as off-normal conditions. The PCS must act on off-normal events and deviations from the target scenario, since certain sequences (chains) of events can precede disruptions. It is important that these decisions are made while maintaining a coherent prioritization between the real-time control tasks to ensure high-performance operation. In this paper, a generic architecture for task-based integrated plasma control is proposed. The architecture is characterized by the separation of state estimation, event detection, decisions and task execution among different algorithms, with standardized signal interfaces. Central to the architecture are a plasma state monitor and supervisory controller. In the plasma state monitor, discrete events in the continuous-valued plasma state are modeled using finite state machines. This provides a high-level representation of the plasma state. The supervisory controller coordinates the execution of multiple plasma control tasks by assigning task priorities, based on the finite states of the plasma and the pulse schedule. These algorithms were implemented on the TCV digital control system and integrated with actuator resource management and existing state estimation algorithms and controllers. The plasma state monitor on TCV can track a multitude of plasma events, related to plasma current, rotating and locked neoclassical tearing modes, and position displacements. In TCV experiments on simultaneous control of plasma pressure, safety factor profile and NTMs using electron cyclotron heating (ECH) and current drive (ECCD), the supervisory controller assigns priorities to the relevant control tasks. The tasks are then executed by feedback controllers and actuator allocation management. This work forms a significant step forward in the ongoing integration of control capabilities in experiments on TCV, in support of tokamak reactor operation

Modelling of the effect of ELMs on fuel retention at the bulk W divertor of JET

Effect of ELMs on fuel retention at the bulk W target of JET ITER-Like Wall was studied with multi-scale calculations. Plasma input parameters were taken from ELMy H-mode plasma experiment. The energetic intra-ELM fuel particles get implanted and create near-surface defects up to depths of few tens of nm, which act as the main fuel trapping sites during ELMs. Clustering of implantation-induced vacancies were found to take place. The incoming flux of inter-ELM plasma particles increases the different filling levels of trapped fuel in defects. The temperature increase of the W target during the pulse increases the fuel detrapping rate. The inter-ELM fuel particle flux refills the partially emptied trapping sites and fills new sites. This leads to a competing effect on the retention and release rates of the implanted particles. At high temperatures the main retention appeared in larger vacancy clusters due to increased clustering rate

The role of ETG modes in JET-ILW pedestals with varying levels of power and fuelling

We present the results of GENE gyrokinetic calculations based on a series of JET-ITER-like-wall (ILW) type I ELMy H-mode discharges operating with similar experimental inputs but at different levels of power and gas fuelling. We show that turbulence due to electron-temperature-gradient (ETGs) modes produces a significant amount of heat flux in four JET-ILW discharges, and, when combined with neoclassical simulations, is able to reproduce the experimental heat flux for the two low gas pulses. The simulations plausibly reproduce the high-gas heat fluxes as well, although power balance analysis is complicated by short ELM cycles. By independently varying the normalised temperature gradients (omega(T)(e)) and normalised density gradients (omega(ne )) around their experimental values, we demonstrate that it is the ratio of these two quantities eta(e) = omega(Te)/omega(ne) that determines the location of the peak in the ETG growth rate and heat flux spectra. The heat flux increases rapidly as eta(e) increases above the experimental point, suggesting that ETGs limit the temperature gradient in these pulses. When quantities are normalised using the minor radius, only increases in omega(Te) produce appreciable increases in the ETG growth rates, as well as the largest increases in turbulent heat flux which follow scalings similar to that of critical balance theory. However, when the heat flux is normalised to the electron gyro-Bohm heat flux using the temperature gradient scale length L-Te, it follows a linear trend in correspondence with previous work by different authors