A study of isometric and pulsed isometric fatigue of the digital flexor muscle group

http://www.worldcat.org/oclc/2834695

Hydroxyethyl starch - the importance of being earnest

Despite ongoing controversial expert discussions the European Medicines Agency (EMA) recently recommended to suspend marketing authorisations for hydroxyethyl starch. This comment critically evaluates the line of arguments. Basically, the only indication for a colloid is intravascular hypovolemia. Crystalloid use appears reasonable to compensate ongoing extracellular losses beyond. In the hemodynamically instable patient this leads to the distinction between an initial resuscitation phase where colloids might be indicated and a crystalloidal maintenance phase thereafter. It is important to bear this in mind when reevaluating the studies the EMA referred to in the context of its recent decision: i) VISEP compared ringer's lactate to 10\% HES 200/0.5 in septic patients and found an increased incidence of renal failure in HES receivers. Unfortunately, study treatment was started only after initial stabilization with HES, randomizing hemodynamically stable patients into a rational (crystalloids) and an irrational (high dose starch until ICU discharge) maintenance treatment. ii) 6S compared ringer's acetate to 6\% HES 130/0.42 for fluid resuscitation in septic patients and found an increased need of renal replacement therapy and a higher mortality in the HES group. However, patients of both groups were again randomized only after initial stabilization with colloids, the actual comparison was, therefore, again rational vs. irrational. Beyond that, the documentation is partly fragmentary, leaving many important questions around the fate of the patients unanswered. iii) CHEST randomized ICU patients to receive saline or 6\% HES 130/0.4 for fluid resuscitation. Actually, despite partly discussed in a different way, this trial showed no relevant differences in outcome. In all, two studies showed what happens to septic patients if starches are used in a way we do not observe in daily practice. The third one actually proves their safety. The benefit of perioperative goal-directed preload optimization using starches is unquestioned. Taking these informations into account, the recommendation of the EMA starches to be generally dangerous remains mysterious and incomprehensible. An authority being able to dictate behavior should stand clear from oppressively ending a worldwide expert discussion and step back into the role of the observer until science achieves an agreement

Reappraising Starling: the physiology of the microcirculation

Purpose of reviewVascular permeability is traditionally explained by Starling's principle, describing two opposing forces across the endothelial cell line to maintain compartments in balance. Several contradictions to this principle have recently questioned its validity.Recent findingsHydraulic conductivity is kept low by a properly working endothelial surface layer, created by binding and intercalating plasma constituents with the structural elements of an endothelial glycocalyx. Limiting fluid filtration is not closely related to the interstitial protein concentration. Rather, the oncotic pressure difference pertinent to fluid homeostasis is built up between the intravascular space and a small protein-free zone beneath the protein-loaded endothelial glycocalyx. This crucial structure, and therefore the resistance of the barrier against outflow of large molecules, is endangered by ischaemia, inflammation and intravascular hypervolaemia. An intact endothelial surface layer retains iso-oncotic preparations of large molecules infused to compensate for acute bleeding. Crystalloids cannot be held back sufficiently, even if preload is warranted.SummaryStarling's principle requires an adaptation to recognize that there is no inward-directed oncotic pressure gradient across the whole anatomical vessel wall. The carrier of vascular barrier competence is the intact endothelial surface layer which might be protected by avoiding intravascular hypervolaemia and limiting inflammation

Twisting and ignoring facts on hydroxyethyl starch is not very helpful

Large randomized trials on critically ill patients have related the use of hydroxyethyl starch (HES) to negative outcomes. In a recent comment we explained in detail why, from our point of view, transferring the results of VISEP, 6S and CHEST into daily ICU practice is as difficult as their extrapolation to perioperative treatment. Haase, Muller and Perner lately challenged this analysis. However, after having carefully read their letter to the editor we are happy to demonstrate that all points we made were absolutely correct. We agree with Haase et al. that a debate on HES safety is important, but has to be based on facts. The difference might be that we like to thoroughly discuss all of them, including the main one: VISEP, 6S and CHEST do not capture the initial stabilization of their hemodynamically instable patients. The vast majority, including those patients later assigned to the "crystalloid" groups, had been stabilized with colloids before study onset. This is not a big problem, but has to be discussed carefully and honestly to prevent the data from being misinterpreted by users and official authorities

Plantar Vein Thrombosis due to Busy Night Duty on Intensive Care Unit

A 32-year-old woman with severe foot pain came to our emergency department after a busy night duty in hospital followed by an extended sleep period. Physical examination revealed a discrete swelling of the medial aspect of the right foot and a painful plantar arch during digital examination. Magnetic resonance imaging (MRI) with intravenous gadolinium showed filling efects in the lateral plantar vein. Doppler sonography displayed noncompressible structures in the plantar veins without flow signals, suggesting a plantar vein thrombosis. Therapy was initiated with low-molecular-weight heparin in combination with customized elastic bandages for the lower leg. Follow-up sonography 6 weeks later showed complete patency of the plantar veins. To our knowledge, we present the first case of isolated plantar vein thrombosis independent of trauma, surgery, or malignant disease, most probably caused by a busy night duty on the intensive care unit (ICU) followed by a prolonged sleeping period

Opioid-induced constipation in intensive care patients: relief in sight?

Constipation is the most common gastrointestinal complication associated with opioid therapy in chronic pain patients, and also frequently occurs in sedated intensive care unit patients. Conventional therapy may not provide sufficient relief from constipation, which can be severe enough to limit opioid use or the dose. In a recent study on terminally ill patients suffering from laxative-resistant opioid-induced constipation, Thomas and colleagues demonstrated subcutaneous methylnaltrexone to rapidly induce defecation. This appealing result might also have favourable prospects for intensive care patients, as their outcome is often codetermined by recovery of bowel functioning

Rapid response pipeline for stabilized subunit vaccines

The Coalition for Epidemic Preparedness Innovations (CEPI) have recently put out a call for proposals aimed at platform technologies that can enable rapid vaccine development for novel or previously unrecognized viruses. We have proposed a streamlined process for the generation of stabilized subunit vaccines. This project brings together unique proprietary recombinant technology for generating stabilized subunit vaccines (the molecular clamp), a highly skilled team from some of Australia’s leading scientific organizations and world-class facilities. Molecular clamp is a broadly applicable platform technology that facilitates expression of recombinant viral glycoproteins in subunit form without loss of native antigenicity. The molecular clamp imparts superior stability over alternative trimerization domains, efficiently stabilizing soluble viral fusion proteins in their native trimeric \u27pre-fusion\u27 form. This form is equivalent to that expressed on the virion surface and the principle target for a protective neutralizing antibody response. Through stabilization of the pre-fusion form, the molecular clamp promotes the production of highly neutralizing and broadly cross-reactive antibodies. Importantly, the molecular clamp does not required prior knowledge of a proteins quaternary structure. Please click Additional Files below to see the full abstract

Heparinase selectively sheds heparan sulphate from the endothelial glycocalyx

A healthy vascular endothelium is coated by the endothelial glycocalyx. Its main constituents are transmembrane syndecans and bound heparan sulphates. This structure maintains the physiological endothelial permeability barrier and prevents leukocyte and platelet adhesion, thereby mitigating inflammation and tissue oedema. Heparinase, a bacteria] analogue to heparanase, is known to attack the glycocalyx. However, the exact extent and specificity of degradation is unresolved. We show by electron microscopy, immunohistological staining and quantitative measurements of the constituent parts, that heparinase selectively sheds heparan sulphate from the glycocalyx, but not the synclecans

Regulation of blood flow and volume exchange across the microcirculation

Oxygen delivery to cells is the basic prerequisite of life. Within the human body, an ingenious oxygen delivery system, comprising steps of convection and diffusion from the upper airways via the lungs and the cardiovascular system to the microvascular area, bridges the gap between oxygen in the outside airspace and the interstitial space around the cells. However, the complexity of this evolutionary development makes us prone to pathophysiological problems. While those problems related to respiration and macrohemodynamics have already been successfully addressed by modern medicine, the pathophysiology of the microcirculation is still often a closed book in daily practice. Nevertheless, here as well, profound physiological understanding is the only key to rational therapeutic decisions. The prime guarantor of tissue oxygenation is tissue blood flow. Therefore, on the premise of intact macrohemodynamics, the microcirculation has three major responsibilities: 1) providing access for oxygenated blood to the tissues and appropriate return of volume;2) maintaining global tissue flood flow, even in the face of changes in central blood pressure;and 3) linking local blood flow to local metabolic needs. It is an intriguing concept of nature to do this mainly by local regulatory mechanisms, impacting primarily on flow resistance, be this via endothelial or direct smooth muscle actions. The final goal of microvascular blood flow per unit of time is to ensure the needed exchange of substances between tissue and blood compartments. The two principle means of accomplishing this are diffusion and filtration. While simple diffusion is the quantitatively most important form of capillary exchange activity for the respiratory gases, water flux across the blood-brain barrier is facilitated via preformed specialized channels, the aquaporines. Beyond that, the vascular barrier is practically nowhere completely tight for water, with paracellular filtration giving rise to generally low but permanent fluid flux outwards into the interstitial space at the microvascular high pressure segment. At the more leaky venular aspect, both filtration and diffusion allow for bidirectional passage of water, nutrients, and waste products. We are just beginning to appreciate that a major factor for maintaining tissue fluid homeostasis appears to be the integrity of the endothelial glycocalyx

Regime heteroskedasticity in Bitcoin: A comparison of Markov switching models

Markov regime-switching (MRS) models, also known as hidden Markov models (HMM), are used extensively to account for regime heteroskedasticity within the returns of financial assets. However, we believe this paper to be one of the first to apply such methodology to the time series of cryptocurrencies. In light of Molnar and Thies (2018) demonstrating that the price data of Bitcoin contained seven distinct volatility regimes, we will �fit a sample of Bitcoin returns with six m-state MRS estimations, with m between 2 and 7. Our aim is to identify the optimal number of states for modelling the regime heteroskedasticity in the price data of Bitcoin. Goodness-of-�fit will be judged using three information criteria, namely: Bayesian (BIC); Hannan-Quinn (HQ); and Akaike (AIC). We determined that the restricted 5-state model generated the optimal estimation for the sample. In addition, we found evidence of volatility clustering, volatility jumps and asymmetric volatility transitions whilst also inferring the persistence of shocks in the price data of Bitcoin