Forward Modeling of Coronal Mass Ejection Flux Ropes in the Inner Heliosphere with 3DCORE.

Forecasting the geomagnetic effects of solar storms, known as coronal mass ejections (CMEs), is currently severely limited by our inability to predict the magnetic field configuration in the CME magnetic core and by observational effects of a single spacecraft trajectory through its 3-D structure. CME magnetic flux ropes can lead to continuous forcing of the energy input to the Earth's magnetosphere by strong and steady southward-pointing magnetic fields. Here we demonstrate in a proof-of-concept way a new approach to predict the southward field B z in a CME flux rope. It combines a novel semiempirical model of CME flux rope magnetic fields (Three-Dimensional Coronal ROpe Ejection) with solar observations and in situ magnetic field data from along the Sun-Earth line. These are provided here by the MESSENGER spacecraft for a CME event on 9-13 July 2013. Three-Dimensional Coronal ROpe Ejection is the first such model that contains the interplanetary propagation and evolution of a 3-D flux rope magnetic field, the observation by a synthetic spacecraft, and the prediction of an index of geomagnetic activity. A counterclockwise rotation of the left-handed erupting CME flux rope in the corona of 30° and a deflection angle of 20° is evident from comparison of solar and coronal observations. The calculated Dst matches reasonably the observed Dst minimum and its time evolution, but the results are highly sensitive to the CME axis orientation. We discuss assumptions and limitations of the method prototype and its potential for real time space weather forecasting and heliospheric data interpretation.

Modeling observations of solar coronal mass ejections with heliospheric imagers verified with the Heliophysics System Observatory.

We present an advance toward accurately predicting the arrivals of coronal mass ejections (CMEs) at the terrestrial planets, including Earth. For the first time, we are able to assess a CME prediction model using data over two thirds of a solar cycle of observations with the Heliophysics System Observatory. We validate modeling results of 1337 CMEs observed with the Solar Terrestrial Relations Observatory (STEREO) heliospheric imagers (HI) (science data) from 8 years of observations by five in situ observing spacecraft. We use the self-similar expansion model for CME fronts assuming 60° longitudinal width, constant speed, and constant propagation direction. With these assumptions we find that 23%-35% of all CMEs that were predicted to hit a certain spacecraft lead to clear in situ signatures, so that for one correct prediction, two to three false alarms would have been issued. In addition, we find that the prediction accuracy does not degrade with the HI longitudinal separation from Earth. Predicted arrival times are on average within 2.6 ± 16.6 h difference of the in situ arrival time, similar to analytical and numerical modeling, and a true skill statistic of 0.21. We also discuss various factors that may improve the accuracy of space weather forecasting using wide-angle heliospheric imager observations. These results form a first-order approximated baseline of the prediction accuracy that is possible with HI and other methods used for data by an operational space weather mission at the Sun-Earth L5 point.

Factors Affecting the Geo-effectiveness of Shocks and Sheaths at 1 AU.

We identify all fast-mode forward shocks, whose sheath regions resulted in a moderate (56 cases) or intense (38 cases) geomagnetic storm during 18.5 years from January 1997 to June 2015. We study their main properties, interplanetary causes and geo-effects. We find that half (49/94) such shocks are associated with interacting coronal mass ejections (CMEs), as they are either shocks propagating into a preceding CME (35 cases) or a shock propagating into the sheath region of a preceding shock (14 cases). About half (22/45) of the shocks driven by isolated transients and which have geo-effective sheaths compress pre-existing southward Bz . Most of the remaining sheaths appear to have planar structures with southward magnetic fields, including some with planar structures consistent with field line draping ahead of the magnetic ejecta. A typical (median) geo-effective shock-sheath structure drives a geomagnetic storm with peak Dst of -88 nT, pushes the subsolar magnetopause location to 6.3 RE, i.e. below geosynchronous orbit and is associated with substorms with a peak AL-index of -1350 nT. There are some important differences between sheaths associated with CME-CME interaction (stronger storms) and those associated with isolated CMEs (stronger compression of the magnetosphere). We detail six case studies of different types of geo-effective shock-sheaths, as well as two events for which there was no geomagnetic storm but other magnetospheric effects. Finally, we discuss our results in terms of space weather forecasting, and potential effects on Earth's radiation belts.

CO-MP4, a polyethylene glycol-conjugated haemoglobin derivative and carbon monoxide carrier that reduces myocardial infarct size in rats.

BACKGROUND AND PURPOSE: MP4 (Hemospan) is a Hb-based oxygen therapeutic agent, based on polyethylene-glycol (PEG) conjugation to Hb, undergoing clinical trials as an oxygen carrier. This study describes the functional interaction between MP4 and carbon monoxide (CO), as a CO delivery agent, and the effects of CO-MP4 on myocardial infarct size following ischaemia and reperfusion in rats. EXPERIMENTAL APPROACH: Kinetic measurements of CO-MP4 binding were used to evaluate the effects of PEG modification on Hb subunit structure/function and to calculate CO-MP4 equilibrium constants. CO transport by CO-MP4 was shown by ligand (O2/CO) partitioning between MP4 and red blood cell (RBC)-Hb. Pharmacological effects of CO-MP4 were studied on myocardial infarction in rats. KEY RESULTS: CO binding kinetics show primary structural/functional effects on beta chains in MP4, with alpha chains maintaining the ability to undergo tertiary conformational transition. CO confers long-term, room-temperature stability and is able to rapidly re-equilibrate between MP4 and RBCs. In a rat model of myocardial infarct, in contrast to oxy-MP4, CO-MP4 reduced infarct size when administered prior to the induction of ischaemia. CONCLUSIONS AND IMPLICATIONS: MP4 PEGylation chemistry modifies the individual function of Hb subunits, but results in an overall CO equilibrium constant similar to that for unmodified Hb. CO-MP4 is able to deliver CO to the circulation and reduces ischaemia/reperfusion injury in rats, providing the first evidence for this drug as a CO therapeutic agent.

A randomized, single-blind, increasing dose safety trial of an oxygen-carrying plasma expander (Hemospan) administered to orthopaedic surgery patients with spinal anaesthesia.

The objective of this study was to further explore the safety of Hemospan (Sangart Inc., San Diego, CA, USA), an oxygen-carrying plasma expander. The aim of this study was to determine if Hemospan is well tolerated in orthopaedic surgery patients with spinal anaesthesia in doses up to 1 L. Hemospan was previously found to be well tolerated in normal volunteers and orthopaedic surgery patients with spinal anaesthesia in doses up to 500 mL. Five cohorts of six orthopaedic surgery patients, American Society of Anesthesiologists (ASA) I and II, were studied. In each cohort, four patients received Hemospan in doses ranging from 200 to 1000 mL, and two received Ringer's lactate immediately prior to induction of spinal anaesthesia. There were no serious adverse events (SAEs). Iohexol clearance measured before and 24 h after dosing was unaffected. There were 14 adverse events (AEs) in the 10 control patients (1.4 per patient) and 30 in the 20 patients receiving Hemospan (1.5 per patient). One patient in the group receiving 200 mL Hemospan had elevated mean arterial pressure after dosing, but there were no elevations in any of the other patients. The peak plasma Hemospan concentration in the 1000 mL group was 1.3 g dL(-1), with a dose-dependent clearance (T(1/2)) ranging from 14.1 to 23.0 h. Plasma methaemoglobin levels were independent of dose, reaching a maximum at 40 h after dosing and never exceeded 0.125 g dL(-1). Troponin T was transiently elevated in two patients receiving Hemospan without symptoms or electrocardiographic abnormalities or elevation of myocardial creatinine kinase isoenzyme. Hemospan was well tolerated in this group of patients at doses up to 1000 mL.

Current status of oxygen carriers ('blood substitutes'): 2006.

An alternative to blood transfusion, based on oxygen-carrying solutions, has been sought for over a century. The present 'first-generation' haemoglobin-products were based on observations that crosslinking with, for example, glutaraldehyde, overcame subunit dissociation and renal toxicity. Experience with these solutions has shown that they can be vasoactive, sometimes increasing blood pressure, sometimes decreasing tissue perfusion and sometimes both. Clinical trials have been disappointing because of unexpected toxicity. The 'second-generation' products are based on a better understanding of the mechanisms of this vasoconstriction. Such products may seem counterintuitive by traditional standards, but it is hoped that they will be less toxic, more beneficial to patients, and more economical to produce.

Current status of blood substitute research: towards a new paradigm.

For many reasons, haemoglobin, modified to prolong its circulation time, seems to be the optimal choice for a cell-free O2 carrier (blood substitute) because of its capacity to reversibly bind O2 in the lung and release it in tissue. After refining methods to prepare highly purified haemoglobin solutions and to chemically or genetically modify haemoglobin to overcome renal toxicity and to prolong retention time, a number of unwanted effects were observed in human clinical trials. These included symptoms referable to the GI tract, elevated pancreatic enzymes and hypertension, presumed to be the result of vasoconstriction. Studies on the mechanism of vasoconstriction induced by haemoglobin, using new techniques to investigate the microcirculation have led to a surprising new paradigm for the design of safe and effective solutions. These include increased O2 affinity (low P50) and increased viscosity and oncotic pressure. These second-generation solutions hold greater promise for clinical development.

Site-specific PEGylation of hemoglobin at Cys-93(beta): correlation between the colligative properties of the PEGylated protein and the length of the conjugated PEG chain.

Increasing the molecular size of acellular hemoglobin (Hb) has been proposed as an approach to reduce its undesirable vasoactive properties. The finding that bovine Hb surface decorated with about 10 copies of PEG5K per tetramer is vasoactive provides support for this concept. The PEGylated bovine Hb has a strikingly larger molecular radius than HbA (1). The colligative properties of the PEGylated bovine Hb are distinct from those of HbA and even polymerized Hb, suggesting a role for the colligative properties of PEGylated Hb in neutralizing the vasoactivity of acellular Hb. To correlate the colligative properties of surface-decorated Hb with the mass of the PEG attached and also its vasoactivity, we have developed a new maleimide-based protocol for the site-specific conjugation of PEG to Hb, taking advantage of the unusually high reactivity of Cys-93(beta) of oxy HbA and the high reactivity of the maleimide to protein thiols. PEG chains of 5, 10, and 20 kDa have been functionalized at one of their hydroxyl groups with a maleidophenyl moiety through a carbamate linkage and used to conjugate the PEG chains at the beta-93 Cys of HbA to generate PEGylated Hbs carrying two copies of PEG (of varying chain length) per tetramer. Homogeneous preparations of (SP-PEG5K)(2)-HbA, (SP-PEG10K)(2)-HbA, and (SP-PEG20K)(2)-HbA have been isolated by ion exchange chromatography. The oxygen affinity of Hb is increased slightly on PEGylation, but the length of the PEG-chain had very little additional influence on the O(2) affinity. Both the hydrodynamic volume and the molecular radius of the Hb increased on surface decoration with PEG and exhibited a linear correlation with the mass of the PEG chain attached. On the other hand, both the viscosity and the colloidal osmotic pressure (COP) of the PEGylated Hbs exhibited an exponential increase with the increase in PEG chain length. In contrast to the molecular volume, viscosity, and COP, the vasoactivity of the PEGylated Hbs was not a direct correlate of the PEG chain length. There appeared to be a threshold for the PEG chain length beyond which the protection against vasoactivity is decreased. These results suggest that the modulation of the vasoactivity of Hb by PEG could be a function of the surface shielding afforded by the PEG, the latter being a function of the disposition of the PEG chain on the protein surface, which in turn is a function of the length of the PEG chain. Thus, the biochemically homogeneous PEGylated Hbs described in the present study, surface-decorated with PEG chains of appropriate size, could serve as potential candidates for Hb-based oxygen carriers.

The role of facilitated diffusion in oxygen transport by cell-free hemoglobins: implications for the design of hemoglobin-based oxygen carriers.

We compared rates of oxygen transport in an in vitro capillary system using red blood cells (RBCs) and cell-free hemoglobins. The axial PO(2) drop down the capillary was calculated using finite-element analysis. RBCs, unmodified hemoglobin (HbA(0)), cross-linked hemoglobin (alpha alpha-Hb) and hemoglobin conjugated to polyethylene-glycol (PEG-Hb) were evaluated. According to their fractional saturation curves, PEG-Hb showed the least desaturation down the capillary, which most closely matched the RBCs; HbA(0) and alpha alpha-Hb showed much greater desaturation. A lumped diffusion parameter, K*, was calculated based on the Fick diffusion equation with a term for facilitated diffusion. The overall rates of oxygen transfer are consistent with hemoglobin diffusion rates according to the Stokes-Einstein Law and with previously measured blood pressure responses in rats. This study provides a conceptual framework for the design of a 'blood substitute' based on mimicking O(2) transport by RBCs to prevent autoregulatory changes in blood flow and pressure.

alphaalpha-crosslinked hemoglobin: was failure predicted by preclinical testing?

In 1998, Baxter Healthcare announced that it was abandoning its product, diaspirin-crosslinked hemoglobin (DCLHb), the first 'blood substitute' to complete all phases of human trials. The company announced that the phase III (pivotal) trials in humans had resulted in an unexpectedly high survival in a group of patients serving as controls for those who received their product in a trauma setting. It is not possible to quantitate the time, efforts and money that were expended in the course of developing this product, from 1985 to 1998. It is rumored that the giant healthcare company had expended more than a half billion dollars on this product, not to mention the investment in the same product by the US Army, the National Institutes of Health and many independent university-based scientists. The disappointment was profound and far-reaching. Although the threat of HIV transmission by banked blood has all but disappeared in the developed world, still the bulk of the world's population faces blood shortages, which this product and its future generations might have helped alleviate. Only Baxter and the Food and Drug Administration may forever know key elements of the history of development of this product. However, because the US Army decided to make its version of the product widely available to scientists, there is a substantial published record, contributed to by both Baxter and independent scientists. Examination of this record leads to the conclusion that there is no single reason for failure. However, it shows that the characteristic hemodynamic response caused by alphaalphaHb increased vascular resistance, and probably eliminates its potential as a red cell substitute. Newer solutions that overcome this limitation should fare better in clinical development when this problem is overcome.

Blood substitutes.

Red cell substitutes are a group of oxygen carriers designed to temporarily replace transfused blood. Each product is unique in its limitations and advantages. Research and development has been slow because of the far-reaching consequences of replacing an oxygen carrier outside of the red cell. Nevertheless, a number of products are in advanced clinical trials and nearing the market. When they are available for use it is likely that development will accelerate and even better products will substantially alleviate the world-wide shortage of blood for transfusion and enable the delivery of medical care to underserved populations. An important consequence of the development of these products has been a better understanding of how oxygen is delivered to tissues.

New transfusion strategies: red cell substitutes.

Red cell substitutes are solutions that can potentially be used in emergencies or during surgery when rapid expansion of the blood volume with an oxygen carrier is needed. The three main types of products in development are based on cell-free hemoglobin, perfluorocarbon emulsions, or liposome-encapsulated hemoglobin. None is currently approved for clinical use, but several are in advanced clinical trials. Outside the red blood cell, hemoglobin is subject to degradation and heme loss. It readily diffuses in the plasma space and effectively scavenges nitric oxide. These properties must be understood and controlled if hemoglobin-based products are to fulfill their promise. The development of red cell substitutes affords us a deeper insight into how oxygen is delivered to tissues in the microcirculation and how blood-flow distribution is regulated within and between organs. As red cell substitutes become available to clinicians and scientists, clinical applications are expected to expand.

Blood substitutes: a review of the literature 1997-1998.

Blood substitutes are oxygen-carrying plasma expanders intended to be used instead of blood. Their development is a long-standing quest and seen as being one of the several most important prizes of biotechnology. Their value, both in the clinic and market place, is virtually limitless. Most of the emphasis today, both in research and development, is on hemoglobin-containing solutions, although modern perfluorocarbon emulsions have considerable advantage over the first-generation products.

The N-terminal sequence affects distant helix interactions in hemoglobin. Implications for mutant proteins from studies on recombinant hemoglobin felix.

The N-terminal 18-amino acid sequence of the beta-chain of hemoglobin, as far as the end of the A helix, has been replaced by the corresponding sequence of the gamma-chain of fetal hemoglobin with the remaining sequence of the beta-chain retained (helices B through H). The gamma-beta-chain had the correct mass, and its entire sequence was established by mass spectrometric analysis of its tryptic peptides; the alpha-chain also had the correct mass. This recombinant hemoglobin (named Hb Felix) retains cooperativity and has an oxygen affinity like that of HbA both in the presence and absence of the allosteric regulators, 2,3-diphosphoglycerate or chloride but differs from HbF in its 2,3-diphosphoglycerate response. However, Hb Felix has some features that resemble fetal hemoglobin, i.e. its significantly decreased tetramer-dimer dissociation and its circular dichroism spectrum, which measure the strength of the tetramer-dimer interface in the oxy conformation and its rearrangement to the deoxy conformation, respectively. Even though Hb Felix contains the HbA amino acids at its tetramer-dimer interface, which is located at a distance from the substitution sites, its interface properties resemble those of HbF. Therefore, the N-terminal sequence and not just those amino acids directly involved at the subunit interface contacts with alpha-chains must have a strong influence on this region of the molecule. The results reinforce the concept of fluid long range relationships among various parts of the hemoglobin tetramer (Dumoulin, A., Manning, L. R., Jenkins, W. T., Winslow, R. M., and Manning, J. M. (1997) J. Biol. Chem. 272, 31326-31332) and demonstrate the importance of the N-terminal sequence, especially in some mutant hemoglobins, in influencing its overall structure by affecting the relationship between helices.

Vascular resistance and the efficacy of red cell substitutes in a rat hemorrhage model.

We have compared polyethylene glycol-modified bovine hemoglobin (PEG-Hb; high O2 affinity, high viscosity, high oncotic pressure) and human hemoglobin cross-linked between the alpha-chains (alpha alpha-Hb; low O2 affinity, low viscosity, low oncotic pressure) with a non-O2-carrying plasma expander (pentastarch, high viscosity and oncotic pressure) after a 50% (by volume) exchange transfusion followed by a severe (60% of blood volume) hemorrhage. Mean arterial pressure and systemic vascular resistance rose significantly in the alpha alpha-Hb but not in the PEG-Hb animals. Two-hour survival was greater in the PEG-Hb animals (93%) than in control (35%), pentastarch (8%), or alpha alpha-Hb (6%) animals. In the PEG-Hb animals, there was no disturbance of acid-base balance, significantly less accumulation of lactic acid, and higher cardiac output than in the other groups. The data suggest that the rise in vascular resistance that follows alpha alpha-Hb exchange transfusion offsets the additional O2 transport provided by the cell-free hemoglobin. When resistance does not rise, as with PEG-Hb, even relatively small amounts of cell-free hemoglobin appear to be a very effective blood replacement.

Heme oxygenase-1-derived carbon monoxide contributes to the suppression of acute hypertensive responses in vivo.

The enzyme heme oxygenase, which exists in inducible (HO-1) and constitutive (HO-2) isoforms, catalyzes the degradation of heme to biliverdin and CO in mammalian tissues. CO has been implicated in the control of vascular tone in a manner similar to that for NO. In the present study, we investigated the contribution of the heme oxygenase/CO pathway to the modulation of acute hypertensive responses in vivo induced by (1) alphaalphaHb, a chemically modified hemoglobin known to scavenge NO, and (2) NG-nitro-L-arginine methyl ester (L-NAME), a competitive NOS inhibitor. Experiments were carried out in conscious rats in which femoral arteries and veins were surgically catheterized 1 or 5 days before treatment with the vasoconstrictor agents. Intravenous infusion of alphaalphaHb (8% solution) or L-NAME (30 micromol/kg) [corrected] produced an acute and significant increase in mean arterial pressure (P<0.05) in rats at 5 days after catheter implantation. In contrast, no change in blood pressure was observed when alphaalphaHb or L-NAME was infused 1 day after the surgical intervention. The suppression of the hypertensive response observed at 1 day after surgery correlated with a significant (P<0.05) HO-1 expression in aorta, heart, and liver as well as increased aortic CO production and cGMP levels. At 1 day after surgery, pretreatment of animals with the heme oxygenase inhibitor zinc protoporphyrin IX (50 micromol/kg IP) markedly decreased aortic CO and cGMP levels and completely restored the vasoconstrictor effects of both alphaalphaHb and L-NAME. These results provide evidence for a crucial role of the heme oxygenase/CO pathway in the regulation of blood pressure under stress conditions in vivo.