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Summary: The pathophysiologic mechanism of sickle cell disease (SCD) involves polymerization of deoxygenated haemoglobin S (HbS), leading to red blood cell (RBC) sickling, decreased RBC deformability, microvascular obstruction, haemolysis, anaemia and downstream clinical complications. Pharmacological increase in the concentration of oxygenated HbS in RBCs has been shown to be a novel approach to inhibit HbS polymerization and reduce RBC sickling and haemolysis. We report that GBT021601, a small molecule that increases HbS‐oxygen affinity, inhibits HbS polymerization and prevents RBC sickling in blood from patients with SCD. Moreover, in a murine model of SCD (SS mice), GBT021601 reduces RBC sickling, improves RBC deformability, prolongs RBC half‐life and restores haemoglobin levels to the normal range, while improving oxygen delivery and increasing tolerance to severe hypoxia. Notably, oral dosing of GBT021601 in animals results in higher levels of Hb occupancy than voxelotor and suggests the feasibility of once‐daily dosing in humans. In summary, GBT021601 improves RBC health and normalizes haemoglobin in SS mice, suggesting that it may be useful for the treatment of SCD. These data are being used as a foundation for clinical research and development of GBT021601. [ABSTRACT FROM AUTHOR]

Background: Electronic health record (EHR) databases provide rich, longitudinal data on interactions with healthcare providers and can be used to advance research into respiratory conditions. However, since these data are primarily collected to support health care delivery, clinical coding can be inconsistent, resulting in inherent challenges in using these data for research purposes. Methods: We systematically searched existing international literature and UK code repositories to find respiratory disease codelists for asthma from January 2018, and chronic obstructive pulmonary disease and respiratory tract infections from January 2020, based on prior searches. Medline searches using key terms provided in article lists. Full-text articles, supplementary files, and reference lists were examined for codelists, and codelists repositories were searched. A reproducible methodology for codelists creation was developed with recommended lists for each disease created based on multidisciplinary expert opinion and previously published literature. Results: Medline searches returned 1126 asthma articles, 70 COPD articles, and 90 respiratory infection articles, with 3%, 22% and 5% including codelists, respectively. Repository searching returned 12 asthma, 23 COPD, and 64 respiratory infection codelists. We have systematically compiled respiratory disease codelists and from these derived recommended lists for use by researchers to find the most up-to-date and relevant respiratory disease codelists that can be tailored to individual research questions. Conclusion: Few published papers include codelists, and where published diverse codelists were used, even when answering similar research questions. Whilst some advances have been made, greater consistency and transparency across studies using routine data to study respiratory diseases are needed. [ABSTRACT FROM AUTHOR]

Ischemia-reperfusion injury increased vascular permeability, resulting in fluid extravasation from the intravascular compartment into the tissue space. Fluid and small protein extravasation lead to increased interstitial fluid pressure and capillary collapse, impairing capillary exchange. Polymerized human serum albumin (PolyHSA) has an increased molecular weight (MW) compared with unpolymerized human serum albumin (HSA) and can improve intravascular fluid retention and recovery from ischemia-reperfusion injury. To test the hypothesis that polymerization of HSA can improve recovery from ischemia-reperfusion injury, we studied how exchange transfusion of 20% of the blood volume with HSA or PolyHSA immediately before reperfusion can affect local ischemic tissue microhemodynamics, vascular integrity, and tissue viability in a hamster dorsal window chamber model. Microvascular flow and functional capillary density were maintained in animals exchanged with PolyHSA compared with HSA. Likewise, exchange transfusion with PolyHSA preserved vascular permeability measured with extravasation of fluorescently labeled dextran. The intravascular retention time of the exchanged PolyHSA was significantly longer compared with the intravascular retention time of HSA. Lastly, the viability of tissue subjected to ischemia-reperfusion injury increased in animals exchanged with PolyHSA compared with HSA. Therefore maintenance of microvascular perfusion, improvement in vascular integrity, and reduction in tissue damage resulting from reperfusion with PolyHSA suggest that PolyHSA is a promising fluid therapy to improve outcomes of ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

Therapeutic agents that increase the Hb affinity for oxygen (O2) could, in theory, lead to decreased O2 release from Hb and impose a hypoxic risk to tissues. In this study, GBT1118, an allosteric modifier of Hb affinity for O2, was used to assess the impact of increasing Hb affinity for O2 on brain tissue oxygenation, blood pressure, heart rate, O2 delivery, and tolerance to hypoxia in Townes transgenic sickle cell disease (SCD) mice. Brain oxygenation and O2 delivery were studied during normoxia and severe hypoxic challenges. Chronic treatment with GBT1118 increased Hb affinity for O2, reducing the PO2 for 50% HbO2 saturation (P50) in SCD mice from 31 mmHg to 18 mmHg. This treatment significantly reduced anemia, increasing hematocrit by 33%, improved cardiac output (CO), and O2 delivery and extraction. Chronically increasing Hb affinity for O2 with GBT1118 preserved cortical O2 tension during normoxia, improved cortical O2 tension during hypoxia, and increased tolerance to severe hypoxia in SCD mice. Independent of hematological changes induced by chronic treatment, a single dose of GBT1118 significantly improved tolerance to hypoxia, highlighting the benefits of increasing Hb affinity for O2 and consequently reducing sickling of RBCs in blood during hypoxia in SCD. [ABSTRACT FROM AUTHOR]

Background: Hemolysis releases toxic cell‐free hemoglobin (Hb), heme, and iron, which overwhelm their natural scavenging mechanisms during acute or chronic hemolytic conditions. This study describes a novel strategy to purify a protein cocktail containing a comprehensive set of scavenger proteins for potential treatment of hemolysis byproducts. Study Design and Methods: Tangential flow filtration was used to purify a protein cocktail from Human Cohn Fraction IV (FIV). A series of in vitro assays were performed to characterize composition and biocompatibility. The in vivo potential for hemolysis byproduct mitigation was assessed in a hamster exchange transfusion model using mechanically hemolyzed blood plasma mixed with the protein cocktail or a control colloid (dextran 70 kDa). Results: A basis of 500 g of FIV yielded 62 ± 9 g of a protein mixture at 170 g/L, which bound to approximately 0.6 mM Hb, 1.2 mM heme, and 1.2 mM iron. This protein cocktail was shown to be biocompatible in vitro with red blood cells and platelets and exhibits nonlinear concentration dependence with respect to viscosity and colloidal osmotic pressure. In vivo assessment of the protein cocktail demonstrated higher iron transport to the liver and spleen and less to the kidney and heart with significantly reduced renal and cardiac inflammation markers and lower kidney and hepatic damage compared to a control colloid. Discussion Taken together, this study provides an effective method for large‐scale production of a protein cocktail suitable for comprehensive reduction of hemolysis‐induced toxicity. [ABSTRACT FROM AUTHOR]

Easy access to high-calorie and fat-dense fast food has resulted in unhealthy dietary and lifestyle changes worldwide, which affects both developed and developing economies. This predisposes populations to a considerable number of metabolic and inflammatory conditions, such as diabetes, nonalcoholic fatty liver disease (NAFLD), and cardiovascular disease (CVD). Guinea pigs have been proposed as a model to study high-fat diet-induced metabolic disease due to their similar antioxidant metabolism and lipid profile to humans, and their susceptibility to atherosclerosis and endothelial disease. This study aims to evaluate cardiovascular and metabolic disorders induced by high-fat high-sucrose diet (HFHSD) in guinea pigs. Two to three-week-old male guinea pigs were fed a normal diet (ND) or HFHSD for 12 wk. Guinea pigs fed a HFHSD developed glucose intolerance, dyslipidemia, and liver, cardiac, and kidney damage. However, hypertension, dysautonomia, endothelial disease, and obesity were absent in these HFHSD guinea pigs. Taken together, these results show that guinea pigs fed a HFHSD are a nonobese model of metabolic disorders, resulting in important cardiac damage. Moreover, our findings suggest that NAFLD may be an important risk factor for diet-induced CVD. NEW & NOTEWORTHY In this study, we show a new animal model for diet-induced disease metabolic disorders without obesity in guinea pigs. Moreover, results suggest a strong relation between liver disease and increased cardiovascular risks. [ABSTRACT FROM AUTHOR]

Microvascular fluid exchange is primarily dependent on Starling forces and both the active and passive myogenic response of arterioles and post‐capillary venules. Arterioles are classically considered resistance vessels, while venules are considered capacitance vessels with high distensibility and low tonic sympathetic stimulation at rest. However, few studies have investigated the effects of modulating interstitial hydrostatic pressure, particularly in the context of hemorrhagic shock. The objective of this study was to investigate the mechanics of arterioles and functional capillary density (FCD) during application of negative tissue interstitial pressure after 40% total blood volume hemorrhagic shock. In this study, we characterized systemic and microcirculatory hemodynamic parameters, including FCD, in hamsters instrumented with a dorsal window chamber and a custom‐designed negative pressure application device via intravital microscopy. In large arterioles, application of negative pressure after hemorrhagic shock resulted in a 13 ± 11% decrease in flow compared with only a 7 ± 9% decrease in flow after hemorrhagic shock alone after 90 minutes. In post‐capillary venules, however, application of negative pressure after hemorrhagic shock resulted in a 31 ± 4% decrease in flow compared with only an 8 ± 5% decrease in flow after hemorrhagic shock alone after 90 minutes. Normalized FCD was observed to significantly improve after application of negative pressure after hemorrhagic shock (0.66 ± 0.02) compared to hemorrhagic shock without application of negative pressure (0.50 ± 0.04). Our study demonstrates that application of negative pressure acutely improves FCD during hemorrhagic shock, though it does not normalize FCD. These results suggest that by increasing the hydrostatic pressure gradient between the microvasculature and interstitium, microvascular perfusion can be transiently restored in the absence of volume resuscitation. This study has significant clinical implications, particularly in negative pressure wound therapy, and offers an alternative mechanism to improve microvascular perfusion during hypovolemic shock. [ABSTRACT FROM AUTHOR]

Background: Hemoglobin (Hb)‐based oxygen (O2) carriers (HBOCs) are being developed as alternatives to red blood cells and blood when these products are unavailable. Clinical trials of previous HBOC generations revealed side effects, including hypertension and vasoconstriction, that were not observed in preclinical studies. Large molecular weight (MW) polymerized bovine Hb (PolybHb) represents a new class of HBOC with promising results. We evaluated the safety profile of PolybHb after an exchange transfusion (ET) in guinea pigs (GPs). This study compares changes in indices of cardiac, inflammatory, and organ function after ET with high (R‐state) and low (T‐state) O2 affinity PolybHb with high MW. Study Design and Methods: Guinea pigs underwent a 20% ET with PolybHb. To assess the implication of PolybHb ET on the microcirculation, hamsters instrumented with a dorsal window chamber were subjected to a similar volume ET. Results: T and R‐state PolybHb did not induce significant alterations in cardiac function. T‐state PolybHb induced mild vasoconstriction shortly after transfusion, while R‐state did not have acute effects on microvascular tone. Conclusion: Large MW PolybHbs were found to be safe and efficacious in increasing O2 carrying capacity and the O2 affinity of the PolybHb did not affect O2 delivery or extraction by tissues in relevant preclinical models. In conclusion, these results suggest that both T‐state and R‐state PolybHb are safe and do not impair O2 delivery. The results are encouraging and support further evaluation of high MW PolybHbs and their future feasibility compared to allogenic blood in a trauma model. [ABSTRACT FROM AUTHOR]

Amelioration of immune overactivity during sepsis is key to restoring hemodynamics, microvascular blood flow, and tissue oxygenation, and in preventing multi-organ dysfunction syndrome. The systemic inflammatory response syndrome that results from sepsis ultimately leads to degradation of the endothelial glycocalyx and subsequently increased vascular leakage. Current fluid resuscitation techniques only transiently improve outcomes in sepsis, and can cause edema. Nitric oxide (NO) treatment for sepsis has shown promise in the past, but implementation is difficult due to the challenges associated with delivery and the transient nature of NO. To address this, we tested the anti-inflammatory efficacy of sustained delivery of exogenous NO using i.v. infused NO releasing nanoparticles (NO-np). The impact of NO-np on microhemodynamics and immune response in a lipopolysaccharide (LPS) induced endotoxemia mouse model was evaluated. NO-np treatment significantly attenuated the pro-inflammatory response by promoting M2 macrophage repolarization, which reduced the presence of pro-inflammatory cytokines in the serum and slowed vascular extravasation. Combined, this resulted in significantly improved microvascular blood flow and 72-h survival of animals treated with NO-np. The results from this study suggest that sustained supplementation of endogenous NO ameliorates and may prevent the morbidities of acute systemic inflammatory conditions. Given that endothelial dysfunction is a common denominator in many acute inflammatory conditions, it is likely that NO enhancement strategies may be useful for the treatment of sepsis and other acute inflammatory insults that trigger severe systemic pro-inflammatory responses and often result in a cytokine storm, as seen in COVID-19. Image 1 • Inflammatory response was reduced with nitric oxide releasing nanoparticles (NO-nps). • Endotoxemia-induced microvascular deficits were alleviated by NO-nps. • NO-nps promoted M2 macrophage repolarization, and reduced M1 macrophage population. • NO-nps could improve outcomes of insults that cause a cytokine storm, like COVID-19. [ABSTRACT FROM AUTHOR]

Alternatives to blood for use in transfusion medicine have been investigated for decades. An ideal alternative should improve oxygen (O2)-carrying capacity and O2 delivery and support microvascular blood flow. Previous studies have shown that large-molecular diameter hemoglobin (Hb)-based oxygen carriers (HBOCs) based on polymerized bovine Hb (PolybHb) reduce the toxicity and vasoconstriction of first-generation HBOCs by increasing blood and plasma viscosity and preserving microvascular perfusion. The objective of this study was to examine the impact of PolybHb concentration and therefore O2-carrying capacity and solution viscosity on resuscitation from hemorrhagic shock in rats. PolybHb was diafiltered on a 500-kDa tangential flow filtration (TFF) module to remove low-molecular weight (MW) PolybHb molecules from the final product. Rats were hemorrhaged and maintained in hypovolemic shock for 30 min before transfusion of PolybHb at 10 g/dL (PHB10), 5 g/dL (PHB5), or 2.5 g/dL (PHB2.5) concentration, to restore blood pressure to 90% of the animal's baseline blood pressure. Resuscitation restored blood pressure and cardiac function in a PolybHb concentration-dependent manner. Parameters indicative of the heart's metabolic activity indicated that the two higher PolybHb concentrations better restored coronary O2 delivery compared with the low concentration evaluated. Markers of organ damage and inflammation were highest for PHB10, whereas PHB5 and PHB2.5 showed similar expression of these markers. These studies indicate that a concentration of ~5 g/dL of PolybHb may be near the optimal concentration to restore cardiac function, preserve organ function, and mitigate the toxicity of PolybHb during resuscitation from hemorrhagic shock. NEW & NOTEWORTHY Large-molecular diameter polymerized bovine hemoglobin avoided vasoconstriction and impairment of cardiac function during resuscitation from hemorrhagic shock that was seen with previous hemoglobin-based O2 carriers by increasing blood viscosity in a concentration-dependent manner. Supplementation of O2-carrying capacity played a smaller role in maintaining cardiac function than increased blood and plasma viscosity. [ABSTRACT FROM AUTHOR]

Acclimatization to hypoxia or high altitude involves physiological adaptation processes, to influence oxygen (O2) transport and utilization. Several natural products, including aromatic aldehydes and isothiocyanates stabilize the R-state of hemoglobin (Hb), increasing Hb-O2 affinity and Hb-O2 saturation. These products are a counter intuitive therapeutic strategy to increase O2 delivery during hypoxia. 5-Hydroxymethylfurfural (5-HMF) is well known Amadori compound formed during the Maillard reaction (the non-enzymatic browning and caramelization of carbohydrate-containing foods after thermal treatment), with well documented effects in Hb-O2 affinity. This study explores the therapeutic potential of 5-HMF on left ventricular (LV) cardiac function (LVCF) during hypoxia. Anesthetized Golden Syrian hamsters received 5-HMF i.v., at 100 mg/kg and were subjected to stepwise increased hypoxia (15, 10, and 5%) every 30 min. LVCF was assessed using a closed chest method with a miniaturized conductance catheter via continuous LV pressure-volume (PV) measurements. Heart hypoxic areas were studied using pimonidazole staining. 5-HMF improved cardiac indices, including stroke volume (SV), cardiac output (CO), ejection fraction (EF), and stroke work (SW) compared to the vehicle group. At 5% O2, SV, CO, EF, and SW were increased by 53, 42, 33, and 51% with 5-HMF relative to vehicle. Heart chronotropic activity was not statistically changed, suggesting that differences in LV-CF during hypoxia by 5-HMF were driven by volume dependent effects. Analysis of coronary blood flow and cardiac muscle metabolism suggest no direct pharmacological effects from 5-HMF, therefore these results can be attributed to 5-HMF-dependent increase in Hb-O2 affinity. These studies establish that naturally occurring aromatic aldehydes, such as 5-HMF, produce modification of hemoglobin oxygen affinity with promising therapeutic potential to increase O2 delivery during hypoxic hypoxia. [ABSTRACT FROM AUTHOR]

In 2013, nearly 15 million units of banked blood were transfused in the United States of America alone. Blood shortages are expected to increase globally. Donated blood is not equal due to differences in quality and deterioration rate. There are no methods to detect time-dependent biochemical and biophysical changes of red blood cells (RBCs) or the deterioration rate of donated RBCs. Nine randomly selected RBC units collected by the San Diego Blood Bank were examined for interdonor variability over six weeks of storage. In vitro RBC quality was assessed weekly by conventional biochemical tests including free Hb, K+, ATP, P50, 2,3 DPG, lactate, and pH. Deformability was measured via cell filtration. Briefly, the RBC suspension (10% Hct), was forced through a 5.0-μm pore membrane (106 mm2) at various flow rates. No interdonor variability in biochemical or mechanical parameters was observed at baseline. Interdonor variability in biochemical properties (free Hb, K+, ATP, P50, 2,3 DPG, lactate, and pH) was observed after 14 days of storage. However, significant differences from baseline in RBC mechanical properties (i.e., filterability) were observed as early as 7 days into storage at the lowest flow rates and after 28 days of storage at all flow rates. There was a net decrease in filterability over time for all donors, but the rate at which filterability decreased (i.e., deterioration rates) was different when comparing individual donors. Changes in all biochemical parameters were significant different between donors. These data suggest that filterability is more sensitive to changes in blood quality than conventional biochemical parameters. [ABSTRACT FROM PUBLISHER]

BACKGROUND: Small rodent models are routinely used to evaluate the safety and efficacy of blood transfusions. Limited comprehensive literature exists about effect of different storage solutions in rat red blood cells (RBCs) characteristics. RBCs undergo time dependent biochemical and biophysical changes during storage known as hypothermic storage lesions (HSLs). OBJECTIVE: This study evaluates the effects of RBC additive solutions (AS) during storage of rat RBCs. METHODS: Blood was leukoreduced and stored as per manufacturer instructions at 4°C up to 42-days. Three solutions, CPDA-1; AS-1; and AS-7 (SOLX), were evaluated. Biochemical parameters measured included extracellular K+, pH, hemolysis, 2,3-diphosphoglycerate (2,3-DPG), oxygen affinity, ATP, and lactate. Mechanical properties measured included RBC deformability, elongation index (EI), RBC membrane shear elastic modulus (SEM), mean corpuscular volume (MCV), viscosity, and aggregability. RESULTS: There were no differences in biochemical or mechanical parameters at baseline or after one week of storage. However, after two weeks, AS-7 preserved biochemical and mechanical properties as compared to CPDA-1 and AS-1. Changes were observed to be significant after 14-days of storage. AS-7 prevented extracellular K+ increase, reduced acidosis, showed lower hemolysis, preserved ATP and 2,3-DPG levels (consequently oxygen affinity), and reduced lactate. AS-7, when compared to CPDA-1 and AS-1, prevented the reduction in RBC deformability and was found to preserve the EI at multiple shear stresses, the membrane SEM, the aggregability and viscosity. DISCUSSION: Rat RBCs stored with AS-7 presented reduced changes in biochemical and mechanical parameters, when compared with rat RBCs stored in CPDA-1 and AS-1, after as early as two weeks of storage. [ABSTRACT FROM AUTHOR]

The term 'anchor baby' refers to children born in the U.S. to undocumented migrant parents who are thought to have been conceived in order to improve their parents' chances of attaining citizenship. Though the term is considered racist and dehumanizing by many, it has recently entered into common usage. This study investigates the process by which this has occurred. We test hypotheses derived from theories of mass and new media using multiple data sources and methods of analysis, and find that the main sources of the anchor baby boom are partisan news websites. The findings suggest that new media may be influencing mass media by creating unique and unprecedented opportunities for medium-sized partisan news organizations. [ABSTRACT FROM AUTHOR]