Critical roles of endogenous glucocorticoids for disease tolerance in malaria

During malaria, the hypothalamic-pituitary-adrenal (HPA) axis is activated and glucocorticoid (GC) levels are increased, but their essential roles have been largely overlooked. GCs are decisive for systemic regulation of vital processes such as immune responses, vascular function, and metabolism, which are crucial in malaria. Here, we introduce GCs in general, followed by their versatile roles for disease tolerance in malaria. A complementary comparison is provided with their role in sepsis. Finally, potential translational implications are considered. The failed clinical trials of dexamethasone against cerebral malaria in the past have diminished the interest in GCs in malaria. However, the issue of relative corticosteroid insufficiency has barely been explored in malaria patients, but may hold promise for a better understanding and treatment of specific malaria complications

Acoustic identification of sentence accent in speakers with dysarthria : cross-population validation and severity related patterns

Dysprosody is a hallmark of dysarthria, which can affect the intelligibility and naturalness of speech. This includes sentence accent, which helps to draw listeners’ attention to important information in the message. Although some studies have investigated this feature, we currently lack properly validated automated procedures that can distinguish between subtle performance differences observed across speakers with dysarthria. This study aims for cross-population validation of a set of acoustic features that have previously been shown to correlate with sentence accent. In addition, the impact of dysarthria severity levels on sentence accent production is investigated. Two groups of adults were analysed (Dutch and English speakers). Fifty-eight participants with dysarthria and 30 healthy control participants (HCP) produced sentences with varying accent positions. All speech samples were evaluated perceptually and analysed acoustically with an algorithm that extracts ten meaningful prosodic features and allows a classification between accented and unaccented syllables based on a linear combination of these parameters. The data were statistically analysed using discriminant analysis. Within the Dutch and English dysarthric population, the algorithm correctly identified 82.8 and 91.9% of the accented target syllables, respectively, indicating that the capacity to discriminate between accented and unaccented syllables in a sentence is consistent with perceptual impressions. Moreover, different strategies for accent production across dysarthria severity levels could be demonstrated, which is an important step toward a better understanding of the nature of the deficit and the automatic classification of dysarthria severity using prosodic features

Study protocol for a randomized controlled trial : prophylactic swallowing exercises in head-and-neck cancer patients treated with (chemo)radiotherapy (PRESTO trial)

Background: Dysphagia is a common and serious complication after (chemo)radiotherapy (CRT) for head-and-neck cancer (HNC) patients. Prophylactic swallowing exercises (PSE) can have a significantly positive effect on post-treatment swallowing function. However, low adherence rates are a key issue in undermining this positive effect. This current randomized trial will investigate the effect of adherence-improving measures on patients' swallowing function, adherence and quality of life (QOL). Methods: This ongoing trial will explore the difference in adherence and swallowing-related outcome variables during and after PSE in HNC patients performing the same therapy schedule, receiving different delivery methods. One hundred and fifty patients treated in various hospitals will be divided into three groups. Group 1 performs PSE at home, group 2 practices at home with continuous counseling through an app and group 3 receives face-to-face therapy by a speech and language pathologist. The exercises consist of tongue-strengthening exercises and chin-tuck against resistance with effortful swallow. The Iowa Oral Performance Instrument and the Swallowing Exercise Aid are used for practicing. Patients are evaluated before, during and after treatment by means of strength measurements, swallowing and QOL questionnaires. Discussion: Since low adherence rates undermine the positive impact of PSE on post-treatment swallowing function, there is need to develop an efficient PSE protocol maximizing adherence rates

Application of Simple Smart Logic for Waterflooding Reservoir Management

A simple smart logic for controlling inflow control valves (ICV) in waterflooding reservoir management is implemented and analyzed, with the final objective of improving the long term financial return of a petroleum reservoir. Such a control is based in a reactive simple logic that responds to the watercut measured in the ICV. Basically, when the watercut increases, the ICV is set to close proportionally. For comparison purposes, four strategies are presented: base case scenario with conventional control, the best completion configuration found by trial-and-error, the reactive control, and a deterministic optimal control based on Nonlinear Gradient Method with adjoint-gradient formulation is shown for comparison purposes. Finally, all four strategies are tested again in different reservoir realizations in order to mimic the geological uncertainties. Two different synthetic reservoir models were studied. First, a simple cube with a five-spot well configuration, in which the permeability field has a horizontal pattern defined by lognormal distributions. The second model is a benchmark proposed by the Dutch university, TU delft, with 101 channelized permeability fields representing river patterns. For the first model, no significant relative gain is found neither in the variable control nor in the optimal control. Manly because of the high homogeneity of the reservoir models. Therefore, no intelligent completion is recommended. On the other hand, for the second and more complex case, the results indicate an expressive relative gain in the use of simple reactive logic. Besides, this type of control achieves results nearly as good as the optimal control. The test in different realizations, however, shows that reservoir characterization is still a key part of any attempt to improve production. Although the variable reactive control is semi-independent, with action being taken based on measurements, some parameters need a priori model to be tuned

Adrenal hormones mediate disease tolerance in malaria

Malaria reduces host fitness and survival by pathogen-mediated damage and inflammation. Disease tolerance mechanisms counter these negative effects without decreasing pathogen load. Here, we demonstrate that in four different mouse models of malaria, adrenal hormones confer disease tolerance and protect against early death, independently of parasitemia. Surprisingly, adrenalectomy differentially affects malaria-induced inflammation by increasing circulating cytokines and inflammation in the brain but not in the liver or lung. Furthermore, without affecting the transcription of hepatic gluconeogenic enzymes, adrenalectomy causes exhaustion of hepatic glycogen and insulin-independent lethal hypoglycemia upon infection. This hypoglycemia is not prevented by glucose administration or TNF-alpha neutralization. In contrast, treatment with a synthetic glucocorticoid (dexamethasone) prevents the hypoglycemia, lowers cerebral cytokine expression and increases survival rates. Overall, we conclude that in malaria, adrenal hormones do not protect against lung and liver inflammation. Instead, they prevent excessive systemic and brain inflammation and severe hypoglycemia, thereby contributing to tolerance

Etiology of lactic acidosis in malaria.

Lactic acidosis and hyperlactatemia are common metabolic disturbances in patients with severe malaria. Lactic acidosis causes physiological adverse effects, which can aggravate the outcome of malaria. Despite its clear association with mortality in malaria patients, the etiology of lactic acidosis is not completely understood. In this review, the possible contributors to lactic acidosis and hyperlactatemia in patients with malaria are discussed. Both increased lactate production and impaired lactate clearance may play a role in the pathogenesis of lactic acidosis. The increased lactate production is caused by several factors, including the metabolism of intraerythrocytic Plasmodium parasites, aerobic glycolysis by activated immune cells, and an increase in anaerobic glycolysis in hypoxic cells and tissues as a consequence of parasite sequestration and anemia. Impaired hepatic and renal lactate clearance, caused by underlying liver and kidney disease, might further aggravate hyperlactatemia. Multiple factors thus participate in the etiology of lactic acidosis in malaria, and further investigations are required to fully understand their relative contributions and the consequences of this major metabolic disturbance

Critical Roles of Endogenous Glucocorticoids for Disease Tolerance in Malaria

During malaria, the hypothalamic-pituitary-adrenal (HPA) axis is activated and glucocorticoid (GC) levels are increased, but their essential roles have been largely overlooked. GCs are decisive for systemic regulation of vital processes such as immune responses, vascular function, and metabolism, which are crucial in malaria. Here, we introduce GCs in general, followed by their versatile roles for disease tolerance in malaria. A complementary comparison is provided with their role in sepsis. Finally, potential translational implications are considered. The failed clinical trials of dexamethasone against cerebral malaria in the past have diminished the interest in GCs in malaria. However, the issue of relative corticosteroid insufficiency has barely been explored in malaria patients, but may hold promise for a better understanding and treatment of specific malaria complications.status: publishe