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Background Methylene blue (MB) was the first synthetic antimalarial to be discovered and was used during the late 19th and early 20th centuries against all types of malaria. MB has been shown to be effective in inhibiting Plasmodium falciparum in culture, in the mouse model and in rhesus monkeys. MB was also shown to have a potent ex vivo activity against drug-resistant isolates of P. falciparum and P. vivax . In preclinical studies, MB acted synergistically with artemisinin derivates and demonstrated a strong effect on gametocyte reduction in P. falciparum . MB has, thus, been considered a potentially useful partner drug for artemisinin-based combination therapy (ACT), particularly when elimination is the final goal. The aim of this study was to review the scientific literature published until early 2017 to summarise existing knowledge on the efficacy and safety of MB in the treatment of malaria. Methods This systematic review followed PRISMA guidelines. Studies reporting on the efficacy and safety of MB were systematically searched for in relevant electronic databases according to a pre-designed search strategy. The search (without language restrictions) was limited to studies of humans published until February 2017. Results Out of 474 studies retrieved, a total of 22 articles reporting on 21 studies were eligible for analysis. The 21 included studies that reported data on 1504 malaria patients (2/3 were children). Older studies were case series and reports on MB monotherapy while recent studies were mainly controlled trials of combination regimens. MB was consistently shown to be highly effective in all endemic areas and demonstrated a strong effect on P. falciparum gametocyte reduction and synergy with ACT. MB treatment was associated with mild urogenital and gastrointestinal symptoms as well as blue coloration of urine. In G6PD-deficient African individuals, MB caused a slight but clinically non-significant haemoglobin reduction. Conclusions More studies are needed to define the effects of MB in P. falciparum malaria in areas outside Africa and against P. vivax malaria. Adding MB to ACT could be a valuable approach for the prevention of resistance development and for transmission reduction in control and elimination programs. Systematic review registration This study is registered at PROSPERO (registration number CRD42017062349 ).

A bstract Key aspects of the AdS/CFT correspondence can be captured in terms of tensor network models on hyperbolic lattices. For tensors fulfilling the matchgate constraint, these have previously been shown to produce disordered boundary states whose site-averaged ground state properties match the translation-invariant critical Ising model. In this work, we substantially sharpen this relationship by deriving disordered local Hamiltonians generalizing the critical Ising model whose ground and low-energy excited states are accurately represented by the matchgate ansatz without any averaging. We show that these Hamiltonians exhibit multi-scale quasiperiodic symmetries captured by an analytical toy model based on layers of the hyperbolic lattice, breaking the conformal symmetries of the critical Ising model in a controlled manner. We provide a direct identification of correlation functions of ground and low-energy excited states between the disordered and translation-invariant models and give numerical evidence that the former approaches the latter in the large bond dimension limit. This establishes tensor networks on regular hyperbolic tilings as an effective tool for the study of conformal field theories. Furthermore, our numerical probes of the bulk parameters corresponding to boundary excited states constitute a first step towards a tensor network bulk-boundary dictionary between regular hyperbolic geometries and critical boundary states.

Abstract Context Vascular insulin resistance is commonly observed in obesity and diabetes; yet, insulin action across the vascular tree and the relationship between insulin responses at different vascular locations remains incompletely defined. Objective To elucidate the impact of elevated free fatty acids (FFAs) on insulin action across the arterial tree and define the relationship among insulin actions in the different arterial segments. Methods This randomized crossover study assigned healthy lean adults to 2 separate admissions with euglycemic insulin clamp superimposed for the final 120 minutes of 5-hour lipid or matched-volume saline infusion. Vascular measures including peripheral and central arterial blood pressure, brachial artery flow-mediated dilation (FMD), carotid femoral pulse wave velocity (cfPWV), augmentation index (AIx), pulse wave separation analysis, subendocardial viability ratio (SEVR), and skeletal and cardiac muscle microvascular perfusion were determined before and after insulin clamp. Insulin-mediated whole body glucose disposal was calculated. Results Insulin enhanced FMD, AIx, reflection magnitude, and cardiac and skeletal muscle microvascular perfusion. Elevation of plasma FFA concentrations to the levels seen in the postabsorptive state in people with insulin resistance suppressed SEVR, blunted insulin-induced increases in FMD and cardiac and skeletal muscle microvascular blood volume, and lowered insulin's ability to reduce AIx and reflection magnitude. In multivariate regression, insulin-mediated muscle microvascular perfusion was independently associated with insulin-mediated FMD and cfPWV. Conclusion Clinically relevant elevation of plasma FFA concentrations induces pan-arterial insulin resistance, the vascular insulin resistance outcomes are interconnected, and insulin-mediated muscle microvascular perfusion associates with cardiovascular disease predictors. Our data provide biologic plausibility whereby a causative relationship between FFAs and cardiovascular disease could exist, and suggest that further attention to interventions that block FFA-mediated vascular insulin resistance may be warranted.

Geologic intervals of sustained warmth such as the mid-Pliocene Warm Period can inform our understanding of future climate change, including the long-term consequences of oceanic uptake of anthropogenic carbon. Here we generate carbon isotope records and synthesize existing records to reconstruct the position of water masses and determine circulation patterns in the deep Pacific Ocean. We show that the mid-depth carbon isotope gradient in the North Pacific was reversed during the mid-Pliocene compared with today, which implies water flowed from north to south and deep water probably formed in the subarctic North Pacific Deep Water. An isotopically enabled climate model that simulates this North Pacific Deep Water reproduces a similar carbon isotope pattern. Modelled levels of dissolved inorganic carbon content in the North Pacific decrease slightly, although the amount of carbon stored in the ocean actually increases by 1.6% relative to modern due to an increase in dissolved inorganic carbon in the surface ocean. Although the modelled Pliocene ocean maintains a carbon budget similar to the present, the change in deep ocean circulation configuration causes pronounced downstream changes in biogeochemistry. Marine carbon isotope patterns point to substantial deep water formation in the North Pacific during the mid-Pliocene Warm Period, according to a synthesis of carbon isotope records and isotope-enabled climate modelling.

Although benign paroxysmal positional vertigo and endolymphatic hydrops are considered to be distinct diagnoses, a minority of vertiginous patients exhibit features of both conditions. This coincidence has been reported previously in the literature, and is reviewed here in terms of possible aetiology. A new hypothesis to account for both conditions is offered, implicating free-floating degenerating debris from the otolithic apparatus. It is postulated that the gelatinous/proteinaceous component may account for an osmotically induced hydrops, while the calcified fragments may induce positional vertigo.

The finite dual $H^{\\circ}$ of an affine commutative-by-finite Hopf algebra H is studied. Such a Hopf algebra H is an extension of an affine commutative Hopf algebra A by a finite dimensional Hopf algebra $\\overline{H}$ . The main theorem gives natural conditions under which $H^{\\circ}$ decomposes as a crossed or smash product of $\\overline{H}^{\\ast}$ by the finite dual $A^{\\circ}$ of A. This decomposition is then further analysed using the Cartier–Gabriel–Kostant theorem to obtain component Hopf subalgebras of $H^{\\circ}$ mapping onto the classical components of $A^{\\circ}$ . The detailed consequences for a number of families of examples are then studied.

Obesity Blunts Insulin-Mediated Microvascular Recruitment in Human Forearm Muscle Lucy H. Clerk , Michelle A. Vincent , Linda A. Jahn , Zhenqi Liu , Jonathan R. Lindner and Eugene J. Barrett From the Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, Charlottesville, Virginia Address correspondence and reprint requests to Eugene J. Barrett, University of Virginia Health System, P.O. Box 801410, 450 Ray C. Hunt Dr., Charlottesville, VA 22908. E-mail: ejb8x{at}virginia.edu Abstract We have previously shown that skeletal muscle capillaries are rapidly recruited by physiological doses of insulin in both humans and animals. This facilitates glucose and insulin delivery to muscle, thus augmenting glucose uptake. In obese rats, both insulin-mediated microvascular recruitment and glucose uptake are diminished; however, this action of insulin has not been studied in obese humans. Here we used contrast ultrasound to measure microvascular blood volume (MBV) (an index of microvascular recruitment) in the forearm flexor muscles of lean and obese adults before and after a 120-min euglycemic-hyperinsulinemic (1 mU · min −1 · kg −1 ) clamp. We also measured brachial artery flow, fasting lipid profile, and anthropomorphic variables. Fasting plasma glucose (5.4 ± 0.1 vs. 5.1 ± 0.1 mmol/l, P = 0.05), insulin (79 ± 11 vs. 38 ± 6 pmol/l, P = 0.003), and percent body fat (44 ± 2 vs. 25 ± 2%, P = 0.001) were higher in the obese than the lean adults. After 2 h of insulin infusion, whole-body glucose infusion rate was significantly lower in the obese versus lean group (19.3 ± 3.2 and 37.4 ± 2.6 μmol · min −1 · kg −1 respectively, P < 0.001). Compared with baseline, insulin increased MBV in the lean (18.7 ± 3.3 to 25.0 ± 4.1, P = 0.019) but not in the obese group (20.4 ± 3.6 to 18.8 ± 3.8, NS). Insulin increased brachial artery diameter and flow in the lean but not in the obese group. We observed a significant, negative correlation between ΔMBV and BMI ( R = −0.482, P = 0.027) in response to insulin. In conclusion, obesity eliminated the insulin-stimulated muscle microvascular recruitment and increased brachial artery blood flow seen in lean individuals. MBV, microvascular blood volume MFV, microvascular flow velocity Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted February 13, 2006. Received October 21, 2005. DIABETES

In healthy humans, insulin at physiological concentrations exerts acute vasodilatory actions on both resistance and terminal arterioles, leading, respectively, to increased total blood flow and the microvascular network volume being perfused. The process of increasing capillary network volume is frequently referred to as “capillary recruitment”. Together these two vascular actions of insulin enhance the delivery of oxygen, nutrients, and insulin itself to tissues. Both processes are diminished by insulin resistance. Here we examined interactions between insulin’s acute (within 2 h) actions on blood pressure (both central and peripheral) and on capillary recruitment in healthy controls and in four distinct groups of people with heightened cardio-metabolic disease (CMD) risk: individuals with obesity, metabolic syndrome, and type 1 or type 2 diabetes. Insulin increased microvascular blood volume (MBV) more effectively in controls than in each of the four CMD risk groups (p < 0.001). Conversely, insulin lowered both central and peripheral systolic pressure (p < 0.05 or less) in each of the CMD risk groups but not in the controls. The insulin-induced blood pressure decrements were greater in the metabolic syndrome, type 2 diabetes, and obesity groups (p < 0.05 or less) than in the controls. The greater blood pressure declines likely reflect decreased sympathetic baroreceptor reflex tone. These effects on blood pressure combined with the diminished dilation of terminal arterioles due to microvascular insulin resistance in the CMD risk subjects led to decreased distal microvascular perfusion as evidenced by changes in MBV. These findings highlight the complex interplay between insulin’s actions on resistance and terminal arterioles in individuals with a high CMD risk, underscoring the importance of addressing microvascular dysfunction in these conditions.

Inflammatory cell infiltration is central to healing after acute myocardial infarction (AMI). The relation of regional inflammation to edema, infarct size (IS), microvascular obstruction (MVO), intramyocardial hemorrhage (IMH), and regional and global LV function is not clear. Here we noninvasively characterized regional inflammation and contractile function in reperfused AMI in pigs using fluorine (19F) cardiovascular magnetic resonance (CMR). Adult anesthetized pigs underwent left anterior descending coronary artery instrumentation with either 90 min occlusion (n = 17) or without occlusion (sham, n = 5). After 3 days, in surviving animals a perfluorooctyl bromide nanoemulsion was infused intravenously to label monocytes/macrophages. At day 6, in vivo 1H-CMR was performed with cine, T2 and T2* weighted imaging, T2 and T1 mapping, perfusion and late gadolinium enhancement followed by 19F-CMR. Pigs were sacrificed for subsequent ex vivo scans and histology. Edema extent was 35 ± 8% and IS was 22 ± 6% of LV mass. Six of ten surviving AMI animals displayed both MVO and IMH (3.3 ± 1.6% and 1.9 ± 0.8% of LV mass). The 19F signal, reflecting the presence and density of monocytes/macrophages, was consistently smaller than edema volume or IS and not apparent in remote areas. The 19F signal-to-noise ratio (SNR) > 8 in the infarct border zone was associated with impaired remote systolic wall thickening. A whole heart value of 19F integral (19F SNR × milliliter) > 200 was related to initial LV remodeling independently of edema, IS, MVO, and IMH. Thus, 19F-CMR quantitatively characterizes regional inflammation after AMI and its relation to edema, IS, MVO, IMH and regional and global LV function and remodeling.

A distinct subgroup of patients, presenting with apparently spontaneous onset of vertigo, is described. Although vestibular evaluation revealed caloric weakness, the proximate cause of vertigo was not labyrinthine dysfunction, but rather the loss of vestibular compensation for an older and previously compensated labyrinthine injury. Instead of addressing the vestibular weakness, effective management needs to focus on the condition that has caused the loss of compensation.