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Science 1998 October 23; 282(5389): 621-622
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Helm Bornson was a paladin of Helm and one of the leaders of the Fellowship of the Purple Staff.[1]
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With the Japanese Imperium at war with the Soviet Union, and the United States watching cautiously on the sidelines, Second Lieutenant Joe Sullivan of the U.S. Marines is sent on a dangerous mission to Tokyo. The Russians have Summoned a demon of epic proportions to attack the city, and all that stands in its deadly path is an untested Japanese super-robot. Now, Joe is at the controls, his gravity-spiking Power at the ready. But that is one huge, mean Demon....
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During intravascular hemolysis in human disease, vasomotor tone and organ perfusion may be impaired by the increased reactivity of cell-free plasma hemoglobin (Hb) with NO. We experimentally produced acute intravascular hemolysis in a canine model in order to test the hypothesis that low levels of decompartmentalized or cell-free plasma Hb will severely reduce NO bioavailability and produce vasomotor instability. Importantly, in this model the total intravascular Hb level is unchanged; only the compartmentalization of Hb within the erythrocyte membrane is disrupted. Using a full-factorial design, we demonstrate that free water–induced intravascular hemolysis produces dose-dependent systemic vasoconstriction and impairs renal function. We find that these physiologic changes are secondary to the stoichiometric oxidation of endogenous NO by cell-free plasma oxyhemoglobin. In this model, 80 ppm of inhaled NO gas oxidized 85–90% of plasma oxyhemoglobin to methemoglobin, thereby inhibiting endogenous NO scavenging by cell-free Hb. As a result, the vasoconstriction caused by acute hemolysis was attenuated and the responsiveness to systemically infused NO donors was restored. These observations confirm that the acute toxicity of intravascular hemolysis occurs secondarily to the accelerated dioxygenation reaction of plasma oxyhemoglobin with endothelium-derived NO to form bioinactive nitrate. These biochemical and physiological studies demonstrate a major role for the intact erythrocyte in NO homeostasis and provide mechanistic support for the existence of a human syndrome of hemolysis-associated NO dysregulation, which may contribute to the vasculopathy of hereditary, acquired, and iatrogenic hemolytic states.
NO is continuously synthesized from endothelium and regulates homeostatic vascular functions such as vasodilation, inhibition of platelet activation and thrombosis, inhibition of endothelial adhesion molecule and endothelin-1 expression, and modulation of intimal and smooth muscle proliferation (1–5). A paradox and controversy in vascular biology surrounds the near diffusion-limited dioxygenation reaction of NO with oxyhemoglobin that oxidizes NO to nitrate, an inactive metabolite (Reaction 1).
Reaction 1
where HbFeII-O2 is ferrous oxyhemoglobin and HbFeIII is methemoglobin.
The rapid (107 M–1 s–1) and irreversible nature of this reaction in the context of an extremely high concentration of intravascular oxyheme groups (10,000 μM) suggests that endothelium-derived NO should be incapable of autocrine diffusion to smooth muscle secondary to rapid inactivation (6–9). Indeed, even hemoglobin (Hb; at 6 μM oxyheme) in buffer completely inhibits endothelium-dependent blood flow in aortic ring bioassays and produces vasoconstriction in vivo (10). It is believed that the compartmentalization of Hb within the erythrocyte limits this inactivation reaction. In vitro studies suggest that combined NO diffusional barriers along the endothelium in laminar flowing blood (11–13), in the unstirred layer around the erythrocyte (14, 15), and in the submembrane protein scaffolding of the erythrocyte (16, 17) reduce the reaction rate of NO with intracellular Hb by 100- to 1,000-fold. In addition to the formation of diffusional barriers, the erythrocyte limits Hb extravasation into the extracellular space (10).
While a physiological role for the erythrocyte in modulating the NO-Hb reaction is supported by the observed vasoconstrictive effects and systemic toxicity of cell-free, Hb–based blood substitutes (6, 7), and is consistent with the endothelial dysfunction recently described in sickle cell disease (18, 19), the idea that hemolysis producing levels of plasma Hb of only 20–150 μM (heme concentration) can significantly affect vascular physiology is not universally accepted. Indeed, a role for Hb in mediating NO scavenging and for the erythrocyte in limiting this process has been challenged on conceptual grounds (20–22). In addition, the primary mechanism for the vasoactivity of cell-free Hb–based blood substitutes remains controversial and has been attributed to both NO scavenging (23) and the premature delivery of oxygen to the systemic arterioles (24, 25), both of which mediate vasoconstriction.
In response to the uncertainty surrounding the relationship between Hb decompartmentalization and NO consumption, we have developed a canine model of intravascular hemolysis to test 3 major hypotheses: (a) simple cellular compartmentalization of Hb within the erythrocyte greatly limits the dioxygenation reaction of Hb with endothelially derived NO; (b) intravascular hemolysis produces a state of resistance to endogenously produced and exogenously delivered NO; and (c) inhaled NO gas will selectively oxidize the plasma HbFeII-O2 to methemoglobin, which will inhibit endogenous NO consumption and systemic vasoconstriction during hemolysis.
Free water–induced hemolysis produces direct intravascular hemolysis, thereby maintaining the same intravascular concentration of Hb during hemolysis. Only the cellular compartmentalization of the Hb is disrupted in these experiments. Model-building experiments demonstrated that the amount of intravascular hemolysis was dependent on the rate and duration of free water infusion (Figure (Figure1A).1A). Infusion rates of 16 ml/kg/h produced steady rises in plasma Hb to concentrations of 200–300 μM (concentration in terms of heme) over a 6-hour infusion. During hemolysis, total Hb levels were unchanged and hematocrit (Hct) was unchanged, reflecting the fact that levels of plasma Hb of 200 μM represent hemolysis of only 2% of all erythrocytes. In this model, cell-free plasma Hb released from the erythrocytes remained 92% HbFeII-O2, and the plasma oxyhemoglobin concentration (in terms of heme) correlated with increased plasma NO consumption in a 1:1 stoichiometric ratio (Figure (Figure11B).
In paired 6-hour pilot experiments, the physiologic responses to 5% dextrose water (D5W) and normal saline were similar (P = NS) and produced no measurable intravascular hemolysis. D5W was chosen as the control fluid for the full-factorial design to control for the hypotonic effects of free water. Consistent with the observed stoichiometric consumption of NO by plasma Hb produced during free water infusion (Figure (Figure1B),1B), free water infusion produced significant increases in mean arterial pressure (MAP) (Figure (Figure1C)1C) and a significant decrease in creatinine clearance over a 6-hour infusion (Figure (Figure1D)1D) compared with control infusions (D5W and normal saline combined).
In order to test the effects of intravascular hemolysis on systemic perfusion and the role of Hb-based NO scavenging as a mechanism for hemodynamic perturbations, full-factorial experiments were performed using 4 experimental interventions (Figure (Figure2).2). In these experiments, hemolysis produced increases in MAP and systemic vascular resistance index (SVRI) and a decrease in cardiac index (CI). Consistent with this effect being mediated by NO scavenging by plasma oxyhemoglobin, there was a significant interaction between the presence or absence of hemolysis and the effects of inhaled NO on MAP (P = 0.0003 for interaction of NO and hemolysis; Figures Figures33 and and4),4), SVRI (P = 0.0003 for interaction of NO and hemolysis; Figure Figure4),4), and CI (P = 0.02 for interaction of NO and hemolysis; data not shown). Inhaled NO attenuated hemolysis-induced increases in MAP and SVRI, and hemolysis induced decreases in CI. In contrast, inhaled NO did not change hemodynamic parameters in nonhemolyzing animals. These data indicate that the effects of inhaled NO during hemolysis were secondary to the direct attenuation of the vasomotor effects of cell-free plasma Hb on the vasculature and not to inhaled NO-induced systemic vasodilatation.
The observed increases in total plasma Hb levels were similar in both groups of hemolyzing animals with and without NO gas inhalation. However, the relationship between increasing MAP and total plasma Hb concentration, and SVRI and total plasma Hb, differed based on the administration of NO gas (P = 0.003 and P = 0.001 respectively; Figure Figure4).4). Thus, as total plasma Hb levels increased, the associated increase in MAP and SVRI was blunted with NO gas inhalation. These results reveal that exogenous NO attenuates the hemodynamic vasopressor effects of hemolysis without changing cell-free Hb levels. This is consistent with an inhibition of the ability of circulating Hb to scavenge systemic NO in the presence of inhaled NO.
Hemolysis also reduced the ability of the kidneys to compensate for infusion-related hyponatremia and led to a decrease in creatinine clearance. This renal dysfunction was attenuated by inhaled NO (P = 0.04 for interaction of NO and hemolysis and P = 0.01 for ordering of the 4 treatment groups; Figure Figure5,5, A and B).
In animals receiving free water infusion (with and without NO gas inhalation), plasma haptoglobin levels rapidly decreased to less than 33% of baseline values during the 6-hour infusion (measured by Western blotting; data not shown).
During free water–induced hemolysis, plasma NO consumption increased in an approximate 1:1 ratio with total plasma Hb levels (Figure (Figure6A).6A). Spectral deconvolution of the plasma Hb species in hemolyzing animals demonstrated that the plasma Hb was 92% HbFeII-O2. In contrast, in hemolyzing animals treated with inhaled NO, there was limited plasma NO consumption despite increasing total Hb levels. Spectral deconvolution of plasma in these animals revealed that the plasma Hb consisted of predominantly methemoglobin in hemolyzing animals receiving inhaled NO. Therefore, inhaled NO attenuated the physiologic effects of free water–induced intravascular hemolysis by altering the ability of the plasma Hb to react with endogenous NO. During hemolysis, oxyhemoglobin consumes endothelium-derived NO and disrupts vasomotor balance. However, the administration of NO maintains vasomotor tone by converting oxyhemoglobin to methemoglobin, which does not consume endothelium-derived NO.
Sodium nitroprusside was administered to all animals during intervention experiments of the full-factorial study of inhaled NO and intravascular hemolysis in order to provide further evidence that plasma Hb released during hemolysis reacts with intravascular NO, thereby leading to systemic vasoconstriction. Sodium nitroprusside decreased SVRI and increased CI in a dose-dependent manner. The presence of hemolysis attenuated the expected vasodilatory response to escalating doses of sodium nitroprusside; however, concomitant inhalation of NO gas restored the expected nitroprusside response toward that of the nonhemolytic controls (P = 0.005 and 0.02 for SVRI and CI, respectively; Figure Figure7).7). Similar but not statistically significant patterns of response to increasing doses of sodium nitroprusside in the 4 treatment groups were also demonstrated for MAP, pulmonary artery pressure (PAP), heart rate (HR), central venous pressure (CVP), and pulmonary capillary wedge pressure (PCWP). In fact, all 7 hemodynamic variables demonstrated the expected ordered responses to nitroprusside (P = 0.008 for 7/7 variables having the same response pattern). These diminished responses of sodium nitroprusside during hemolysis support the hypothesis that cell-free plasma Hb consumes NO within the vasculature during intravascular hemolysis. These results may also, in part, be explained by the direct reaction of sodium nitroprusside with oxyhemoglobin (26).
In a second model using direct infusions of canine Hb preparations, plasma Hb significantly increased SVRI and pulmonary vascular resistance index (PVRI), and inhaled NO attenuated Hb-induced increases in SVRI and PVRI (Figure (Figure8).8). In animals breathing air, plasma Hb remained predominantly oxyhemoglobin over the course of the infusion. In contrast, in animals breathing NO, the plasma Hb was converted to predominantly methemoglobin over the course of the infusion. In the animals breathing NO, there was a higher concentration of methemoglobin in the systemic arterial circulation than in the pulmonary circulation (mean difference, 4.5%; 95% confidence interval, –0.6% to 9.7%; P = 0.07), suggesting that the conversion of oxyhemoglobin to methemoglobin was occurring in the pulmonary circulation at the site of NO inhalation.
We developed 2 canine models of intravascular hemolysis in order to obtain mechanistic insight into the relationship among cell-free plasma Hb, NO bioavailability, and the systemic manifestations that can occur with Hb-mediated NO consumption. Importantly, in the first model, the total intravascular Hb level is unchanged; only the compartmentalization of Hb within the erythrocyte membrane is disrupted. These experiments demonstrated that hemolysis produces dose-dependent vasoconstriction and impaired renal function secondary to the stoichiometric oxidation of endogenous and exogenous NO by cell-free plasma oxyhemoglobin. Importantly, 80 ppm inhaled NO gas oxidized 85–90% of the plasma oxyhemoglobin to methemoglobin, which inhibited endogenous NO scavenging, prevented systemic vasoconstriction, and restored responsiveness to systemically infused NO donors. This observation confirms that the observed physiological effects of hemolysis are directly mediated by the dioxygenation reaction of ferrous oxyhemoglobin and NO (Reaction 1). These studies provide evidence for the existence of a syndrome of hemolysis-associated endothelial dysfunction and suggest a potential therapeutic role of inhaled NO for iatrogenic, acquired, and hereditary hemolytic diseases. Specifically, the consumption and loss of NO activity during intravascular hemolysis may contribute to clinical signs and symptoms attributable to vasomotor instability that may be ameliorated by NO gas inhalation.
The levels of plasma Hb produced in the present study (with concentration expressed in terms of heme group) are within the ranges observed in human disease states. For example, in patients with sickle cell disease, the levels of plasma oxyheme range from 2 to 20 μM, with mean levels of 4 μM (18). During vasoocclusive crisis, levels can rise to 20–40 μM (27). Intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria produces abdominal pain, gastric and esophageal dystonia, and erectile dysfunction, with levels of plasma Hb ranging from 30 to 120 μM (in heme concentration) and up to 600 μM during paroxysms of hemolysis (28). During cardiopulmonary bypass, the levels of plasma oxyheme can rise to 150 μM (29–32). The present studies suggest that these pathologically relevant levels of hemoglobinemia may be associated with endogenous NO inhibition, a vasopressor effect, and impaired organ function.
The biochemical and physiologic disturbances that occur during intravascular hemolysis are related to the disruption of diffusional barriers that typically regulate the reaction of intra-erythrocytic Hb with NO (11–17). Cell-free plasma Hb can react with endothelial cell–produced NO at nearly diffusion-limited rates, resulting in the rapid dioxygenation of NO by Hb with the formation of nitrate and methemoglobin (6–9). These rapid reactions greatly limit the diffusion of NO from endothelium to smooth muscle. Consequently, smooth muscle guanylyl cyclase is not activated, and vascular relaxation and vasodilation are inhibited (33). Additionally, cell-free plasma Hb can rapidly extravasate into the spaces between endothelial and smooth muscles cells and further scavenge NO, thereby prohibiting it from diffusing into smooth muscle cells (10). This mechanism is supported by the observed decrease in hypertensive effects of the Hb-based blood substitutes as molecular weight increases (7, 23) and the decrease in NO scavenging effects of the high-molecular-weight haptoglobin-Hb complex, compared with non–haptoglobin-bound Hb (34). We have proposed that the formation of Hb-haptoglobin high-molecular-weight multimers serves to limit such extravasation during physiologic intravascular hemolysis (35).
NO scavenging by cell-free plasma Hb may have contributed to the increased morbidity and mortality observed in studies of stroma-free Hb artificial blood substitute solutions (7). The administration of the blood substitute solutions in preclinical and clinical trials led to pulmonary and systemic hypertension, increased systemic vascular resistance, decreased organ perfusion, gastrointestinal spasm and dysmotility, and death (7, 36–43). While studies of new generation Hb-based blood substitutes with heme pocket mutations designed to decrease the heme reactivity with NO have shown reduced vasopressor effects (6), other investigators have suggested that the vasoconstrictor effects of Hb-based blood substitutes occur secondarily to premature oxygen unloading at the precapillary sphincter (24, 25). The current study provides additional evidence that NO consumption by oxyhemoglobin is a mechanism of cell-free Hb–mediated vasoconstriction and may contribute to the adverse effects observed in the blood substitute trials and during intravascular hemolysis in human disease.
In chronic hereditary hemolytic diseases such as sickle cell anemia, clinical complications such as pulmonary hypertension, priapism, leg ulcerations, and stroke may be in part related to repeated episodes of intravascular hemolysis with consequent increased NO scavenging, vasoconstriction, and end-organ hypoperfusion (18, 19, 44). In patients with sickle cell disease, chronic hemolysis leads to the destruction of approximately 10% of the circulating erythrocytes every 24 hours, with 30% of this hemolysis estimated to be intravascular (18, 45). The Hb scavenging system in these patients becomes saturated, as indicated by undetectable plasma haptoglobin levels, and cell-free plasma Hb accumulates, as has been demonstrated by increased levels of plasma Hb in patients with sickle cell disease compared with normal patients (18). The plasma of these patients consumes significantly more NO than the plasma of normal patients, and the amount of NO consumption correlates with the plasma heme levels (18). Consistent with an NO-scavenging effect of increased cell-free plasma Hb, the vasodilatory responses to nitroprusside, nitroglycerin, and other NO donors are significantly blunted in sickle cell patients and in sickle cell transgenic mouse models (18, 19, 46–48). Scavenging of NO by cell-free plasma Hb may be involved in the pathophysiologic vasculopathy and prothrombotic state that occur in many chronic hereditary hemolytic diseases such as sickle cell disease and thalassemia (18, 19, 46–54) and acute hemolytic disease states, such as prolonged cardiopulmonary bypass, thrombotic thrombocytopenic purpura, and malaria. These studies provide further evidence that inhaled NO therapy may attenuate the NO-scavenging effects of cell-free plasma Hb and may be able to block the pathophysiologic changes that occur during iatrogenic (cardiopulmonary bypass) or disease-specific (sickle cell pain crisis, malaria, etc.) intravascular hemolysis in many human diseases. Further research is required to assess the contribution of hemolysis and therapeutic utility of inhaled NO therapy in hereditary and iatrogenic hemolytic disorders.
In conclusion, these data provide controlled in vivo evidence that NO scavenging by cell-free plasma Hb during intravascular hemolysis disrupts endothelial NO-dependent vasomotor function and produces systemic physiologic changes and organ dysfunction, which are attenuated by inhaled NO therapy. These biochemical and physiological studies support the existence of a syndrome of hemolysis-associated endothelial dysfunction, which may contribute to the vasculopathy of hereditary, acquired, and iatrogenic hemolytic states. Furthermore, these studies support a potential therapeutic role for NO donor agents in preventing the end-organ injury associated with these disease states.
All experiments were approved by the Animal Care and Use Committee of the Clinical Center of the NIH. In all, 32 purpose-bred beagles (12–28 months, 9–12 kg) were studied.
All procedures were performed after the induction of anesthesia with halothane (1–4%) and the initiation of mechanical ventilation. Once all procedures were finished, the halogenated gas was terminated, and 100% oxygen administered until the dog emerged from anesthesia. The dog was then maintained on continuous sedation with intravenous medetomidine (2–5 μg/kg/h) and received continuous intravenous analgesia with fentanyl (5–15 μg/kg/h). The animals were monitored continuously, and all signs of pain and distress were evaluated immediately and the infusions adjusted appropriately.
A canine model of free water–induced intravascular hemolysis was developed to determine the optimal dose of free water administration that produced clinically relevant levels of cell-free plasma Hb (20–300 μM heme), simulating an acute hemolytic episode. Increasing rates of free water (2, 4, 8, 16 ml/kg/h) were administered intravenously through a central venous catheter to 4 animals over 6 hours in order to characterize the relationship between the rate of free water infusion and plasma concentration of cell-free Hb. Subsequent experiments were performed (n = 8) to determine the ideal control fluid to be used in the full-factorial design as well as to delineate the biochemical and pathophysiologic effects of acute intravascular hemolysis in our model. In these pilot experiments, each animal received a 6-hour baseline infusion of 1 of 2 potential control group fluids through the central venous catheter (n = 4, 0.9% sodium chloride; n = 4, D5W) followed 1 week later by a 6-hour infusion of free water through a central venous catheter. Based on these pilot experiments, a free water infusion rate of 16 ml/kg/h was chosen to achieve the desired rate of intravascular hemolysis. While there was no difference in the hemodynamic responses to either control fluid, 0.9% sodium chloride or D5W, we chose the latter to control for any potential hypotonic effects of free water infusion.
This set of experiments examined the effects of inhaled NO gas and oxidation of plasma oxyhemoglobin to methemoglobin on the biochemical and physiologic changes caused by intravascular hemolysis. Paired experiments were performed in 20 tracheostomized animals (5 per group) and included a 6-hour baseline study with infusion of D5W through a central venous catheter followed 1 week later by a 6-hour intervention study with infusion of either D5W or free water through a central venous catheter with or without inhaled NO (Figure (Figure1).1). All animals received 21% fraction inspired oxygen (FiO2) through tracheostomy using an air/oxygen blender. Eighty ppm NO gas with 21% FiO2 was simultaneously administered to animals randomized to receive NO therapy. In order to determine the vascular responsiveness to exogenous NO in the presence and absence of hemolysis and inhaled NO, all animals received a 20-minute infusion of escalating doses of sodium nitroprusside, a direct NO donor (1, 3, 9, and 27 μg/kg/min) at 5-minute intervals prior to the conclusion of the study.
For all studies, femoral arterial (20-gauge) and external jugular venous (8 French) catheters (Maxxim Medical) were placed percutaneously under anesthesia using aseptic sterile technique. MAP and HR were obtained from the femoral artery catheter tracing. Additionally, a pulmonary artery thermodilution catheter (7 French; Abbott Critical Care Systems, Abbott Laboratories) was introduced through the external jugular vein catheter in order to obtain cardiac output (CO), CI, PAP, PCWP, and CVP measurements. Urinary catheters (12 French) were placed during each study under anesthesia using aseptic technique. All catheter placements were performed under general anesthesia. At the end of the first week's fluid control experiments, all catheters were removed, and the animals recovered. At the end of the second week's intervention experiments, all animals were euthanized.
In all experiments, hemodynamic measurements (MAP, CVP, PAP, CO, and PCWP) and laboratory studies (analysis of Hct, Hb, and serum chemistries; arterial blood gas analysis; spectrophotometric-based quantification of cell-free Hb concentration; and chemiluminescence-based assays of NO consumption) were obtained at 0-, 1.5-, 3.0-, 4.5-, and 6.0-hour time points. Urine was collected from 0 to 6 hours to measure 6-hour creatinine clearances. Hemodynamic measurements were also obtained at the end of each 5-minute interval of sodium nitroprusside infusion at doses of 1, 3, 9, and 27 μg/kg/min.
The contribution of cell-free Hb to the physiologic findings in our water infusion model cannot be completely isolated, because this model simulates an acute episode of intravascular hemolysis with the release of erythrocyte membrane and all cellular contents into the plasma. Also, the hypotonic swelling of the erythrocytes in our model does not always lead to cell lysis and may have contributed to the physiologic alterations in our model. Therefore, to confirm and extend the findings of the intravascular water infusion model, additional experiments were performed with infusion of 99% pure Hb solutions directly into the animals. Canine whole blood was collected and diluted with PBS buffer (1:2). The blood was frozen and thawed 3 times and then centrifuged at 82,000 g for 1 hour at 4°C to remove the membrane fraction. The supernatant was collected and filtered (0.22 μM). Hb concentrations were measured, and the solutions were stored at 4°C until infusion. Prior to infusion, each solution underwent a second filtration (0.22 μM). These additional experiments allowed for direct measurements of the physiologic and biochemical effects of cell-free Hb infusion with and without inhaled NO exposure. Hb solutions were infused into animals breathing air (n = 2) or 80 ppm NO (n = 2) for 1 hour. Serial physiologic and biochemical measurements were obtained.
The ability of plasma to consume NO was measured with a previously published and validated NO consumption assay using an NO chemiluminescence analyzer (Sievers 280i NO analyzer; GE Analytical Instruments) as previously described (35). Total plasma Hb concentration (expressed in terms of heme groups; division by 4 gives Hb concentration) was measured by visible absorbance spectrophotometry (HP8453 UV-Vis Diode Array Spectrophotometer; Hewlett-Packard). The concentrations of oxyhemoglobin and methemoglobin were analyzed by deconvoluting the spectrum into components from basis spectra of canine Hb composed of oxyhemoglobin and methemoglobin in PBS buffer using a least-square method similar to that previously described, with subtraction of background plasma scattering (55). Plasma haptoglobin levels were measured using a polyclonal anti-human haptoglobin antibody (Sigma-Aldrich) as previously described (18).
Pilot data were analyzed using ANOVA, with main effects for study (baseline and hemolysis), time, and animal, and a 2-way interaction between study and time. The full-factorial treatment experiments were analyzed using ANOVA, with main effects for study (baseline and intervention), 4 treatment arms, time, and animal (nested within each of the 4 arms). Two- and 3-way interactions, not involving animal, were included in the model. Analysis of responses to sodium nitroprusside were performed using ANOVA on percent change in hemodynamic variables with increasing dose in the intervention study with main effects for the 4 treatment arms, dose, and animal (nested within each of the 4 arms). Two-way interactions, not involving animal, were included in the model. Analysis of differences in creatinine clearance during the intervention study was performed using a nonparametric test for ordered alternatives based on the a priori hypothesis that free water would decrease creatinine clearance and that inhaled NO would attenuate this decrease (Jonckheere-Terpstra test) (56). Comparisons of the 2 groups of animals in the confirmatory Hb infusion experiments were performed with ANOVA with main effects for treatment group and time and a 2-way interaction term. All values are represented in the figures as mean ± SEM, and all Hb concentrations are expressed in terms of heme groups. P < 0.05 was considered statistically significant.
This study was funded by intramural sources at the NHLBI and the Critical Care Medicine Department, Clinical Center at the NIH. We gratefully thank INO Therapeutics for supplying the NO gas and delivery systems for this study.
Peter C. Minneci and Katherine J. Deans contributed equally to this work.
Mark T. Gladwin and Steven B. Solomon are co-senior authors.
Nonstandard abbreviations used: CI, cardiac index; CVP, central venous pressure; D5W, 5% dextrose water; Hb, hemoglobin; HbFeII-O2, ferrous oxyhemoglobin; MAP, mean arterial pressure; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; SVRI, systemic vascular resistance index.
Conflict of interest: The authors have declared that no conflict of interest exists.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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Bike Exchange Closed to Customers in July
The New Brunswick Bike Exchange will be closed to the public for the month
of July. While we're away, we will be working hard to replenish our stock
of bikes for sale! Volunteers are still welcome during this time. If you
are interested in volunteering, please e-mail Leighann at
Bike essentials for beginners
Thinking about start biking? Did you just picked up a bike but don't know what else you need? Fear no more. The folks at Gizmodo put together a list of essentials items and advice for beginners to give an idea.
How to prevent your bike to get stolen?
It happens to everyone at least one: Getting you bikes stolen. It is not fun. It is irritating. It is just wrong. Although there is no 100% safe way to lock your bike, there are ways to deter would be thieves from choosing your bike to be their next target. We found this article "5 Steps to Effective Bike Security" in the BIKE ROOTS blog, to be very helpful. Check out our Useful Links page for bike registration advise.
Updated Hours:
We are close for the summer in July.
Our hours starting on August will be as follows:
Tuesdays, 6-8pm
Thursdays, 6-8pm
Saturdays ** Please check with our Facebook page for Saturday hours **
Check back often to see what are we upto!
If you want to get involved in the Bike Exchange there are a couple ways of doing so:
- Organize and/or host a bike drive in your community, workplace, church, softball league, or anywhere else. If you're willing to put the word out to your community, we will provide support for the drive including brochures, fliers, and transportation for the donated bikes back to our warehouse.
- Get involved through volunteering in our shop, located in the warehouse at PRAB's 90 Jersey Avenue facility. No mechanic experience is necessary and there is a wide variety of volunteer roles. We need all types of volunteers, including cashiers, salespeople, accountants, mechanics, and bike drive coordinators. Check out our Volunteering page for more details.
Have any more questions? Send us an email at firstname.lastname@example.com and we'll get back to you as soon as we can. If you want to host a bike drive, contact us at email@example.com.
PRAB is a comprehensive Human Services Organization in Middlesex County, New Jersey that provides a comprehensive range of essential services for children, youth, families and senior citizens. For more information on PRAB, click their logo.
Hope to see you around the shop!


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The Holiday Season Worksheets and Printables
Usher in the holidays with an abundance of Holiday Season worksheets that will bring joy and cheer to each learning moment. Enjoy a wide variety of Holiday Season printables that include fun decorations and holiday cards for the New Year, winter, Christmas, Hanukkah, Kwanzaa, as well as holiday math and reading to keep brains active during the break. Wrap up the holiday season with New Years worksheets.
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Current Filters (99 results):
The Holiday Season
Christmas List for Santa
Has your little one been nice this year? Give him this colorful template to write out his Christmas list for Santa!
Christmas Writing Activity
Do you remember your favorite Christmas experience? Get your little writer to practice her creative writing with a fun prompt.
Year of the Dragon Coloring Page
Get ready to ring in the New Year, 2012, the year of the dragon! Enjoy a festive coloring page with your child, and add some Christmas colors to the scene.
Get into the spirit of the holidays with this Greensleeves print! This print features the lyrics to the Christmas song Greensleeves against a pretty background.
Make a Holiday Card: Hanukkah Sufganiyot
Full of sufganiyot, jelly-filled doughnuts that are a traditional Hanukkah treat, this card is a tasty way to celebrate the holiday.
Christmas Picture Sudoku
This Christmas brainteaser features two pages of colorful medium-level picture Sudoku for young kids.
Gingerbread Woman Pattern
This holiday season, use this gingerbread woman pattern for cookies, sewing projects, or crafts. Trace the pattern onto sturdy cardboard or a cereal box.
Christmas Cookie Sudoku
If your child is done with easy- and medium-level picture Sudoku maybe she's ready for this one.
Holiday Story Cards
Get into the holiday spirit with a little storytelling! These holiday story cards are the perfect way to help your little writer find her voice.
Hanukkah Decorations
Hanukkah decorations don't have to be complicated. Make these Hanukkah decorations with your young crafter this winter.
Christmas Card Coloring
Let your little angels help decorate these DIY holiday greeting cards! Simply print and fold, then add color and glitter for a sparkly, homemade card.
Auld Lang Syne Print
Sing along to "Auld Lang Syne" with this festive print, featuring the lyrics to the classic Scottish tune. Ring in the new year with "Auld Lang Syne!"
Printable Holiday Gift Tags
These color-your-own holiday gift tags are a fun activity to share with your little one. He'll love to help you color and decorate them.
Silent Night
Silent night, holy night, all is calm, all is bright! This printable displays the first two lines of the classic Christmas carol over a pretty background.
Countdown to Hanukkah
Countdown to Hanukkah with this fun menorah worksheet. You can countdown to Hanukkah by adding paper flames on each menorah candle.
Kwanzaa Coloring Page
Color in the kinara candles of Kwanzaa with help from a color-by-number chart.
Angel Christmas Card
This angel Christmas card is easy to make and fun to give. Color and fold an angel Christmas card with your little one this holiday season.
Christmas Tree Coloring
Put a little color in your Christmas cheer! Share this Christmas tree coloring page with your little sugar plum.
Hanukkah Color by Number
This Hanukkah color celebrates Hanukkah with the bright lights of a Menorah. Bring this festive holiday to life with this Hanukkah color-by-number.
Winter Writing Prompt
Do Christmas angels play hockey? Use your imagination to elaborate on this wacky winter scene!
Make a Holiday Card: Happy Chanukah in Hebrew
Celebrate the Festival of Lights by sending a homemade Chanukah greeting to someone special.
Victorian Christmas Scene
Celebrate a traditional Christmas with Victorian decorations. Use color to bring this Victorian Christmas scene to life!


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Net Neutrality, Serious Business for Bloggers
I've been reading a lot about Net Neutrality lately, and I will be the first to admit that it is a complex topic and I don't pretend to have all the answers.
But Net Neutrality is a serious subject that will affect all bloggers, and if it means keeping control from the reach of big corporations then I'm all for it.
Here is one of the better explanations that I've come across about the topic. Tim Berners-Lee, inventor of the Web tells us it is not about the cost of the service. It is really about the control of information.
Let's see whether the United States is capable as acting according to its important values, or whether it is, as so many people are saying, run by the misguided short-term interested of large corporations.
Rocketboom also has a good video.
Related links: blog bloke, instabloke, blog, weblog, blogging, web 2.0, internet, computers and internet, technology, tech, business, net neutrality


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Norfolk Nelson MuseumSouth Quay, Great Yarmouth
Time And Tide Museum Of Great Yarmouth LifeBlackfriars Road
Merrivale Model VillageMarine Parade, Great Yarmouth
Lowestoft Maritime MuseumWhapload Road
Lowestoft MuseumBroad House Nicholas Everitt Park
East Anglia Transport MuseumChapel Road, Lowestoft
Beccles & District Museum
Bungay MuseumBroad Street
It's here! We announce our annual top 100 cultural contributors in Scotland. Check out who made the cut


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Maison Martin Margiela
Black Maison Martin Margiela Leather Knee High Heeled Boots
Black leather knee high heeled boots from Maison Martin Margiela. This sleek boot can be pulled on for easy wear. Brown stacked chunky heel and almond toe. Perfect to pair with dark wash skinny jeans and leather jacket.
Size: 40
Made in: Italy
Color: Black
Content: Leather
Condition: Pre-owned. This item is in good condition. Due to the nature of leather, wrinkling is present. Moderate wrinkling at upper vamp at the natural bend of the foot. Distressing in leather at seams of boots may be an intentional element, however, cannot confirm. A few small white markings at middle of both boot shafts. Scratches in leather present at front vamp and counter vamp of boots. Heavier wear on outsoles.
- Heel: 3"
- Total Height: 18.5"
- Circumference: 15.75"
- Outsole Length: Approx. 12"
- Outsole Width: 3.75"
RETURNS: We accept returns of clothing and shoes when notified via email to email@example.com within 3 days of receiving the item/items. Handbags, accessories and jewelry are final sales. We only accept returns on these items if they are in the condition they were received. Items must have original Luxury Garage Sale tags and be unworn.
SHIPPING: Standard shipping in the Continental US is free via FedEx Ground. Second Day Air is $25 and next-day air is $45. International shipments are a flat rate of $45.
- All
- Black Friday 2016
- Boots and Booties
- Boots
- Black
- Pre-Owned
- Maison Martin Margiela
- Designers
- Frontpage
- Maison Martin Margiela
- New Arrivals
- $200-500
- Shoes
- Size 10-10.5
- 10, 40


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hallo i am nicole, i have 23 years and i just wait to meet you.
No reality you're the lucky ones, because she has an amazing body and legs that go all the way up to her ass… But her real quality is her personality. Yes she can be sensual and giving because some guys love that girlfriend type experience……But she can also take control if the situation demands!
NICOLL Long is a rare Exotic Beauty! Treat her with respect (the same respect we know you will show all our girls) and we guarantee she will make sure the time you spend with her is full of fun, laughter and the sensuality you deserve from a high class Busty Latino Escort
24h/7 days


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From GoneRaw.com
- Yield
- 4 servings
- 2 creamy avocados
- 1 tbls dulse flakes
- 1 head broccoli, broken into small pieces
- 1 tbls sunflower seeds
- 4 stalks celery, finely chopped
- Mix the mashed avocados with the seaweed and broccoli. Sprinkle the sunflower seeds on top, and place the finely chopped celery in the center of the dish. Serve in individual dishes with a light salad or use the mixture as a filing for a simple pecan and date base.
Nutritional Info
- Calories213
- Carbohydrates17 g(6%)
- Fat16 g(25%)
- Protein6 g(11%)
- Saturated Fat2 g(11%)
- Sodium57 mg(2%)
- Polyunsaturated Fat2 g
- Fiber10 g(40%)
- Monounsaturated Fat10 g


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Nowadays, the name Johnny Mathis likely brings about thoughts of Christmas and the many holiday songs Mathis covered throughout his career. Mathis first became popular in the 1950s, primarily singing jazz tunes and ballads. His most successful hits were "Chances Are" in 1957 and "Too Much, Too Little, Too Late" in 1978, both reaching #1 on the US charts. Prior to singing, Mathis was a world class high-jumper, being invited to the Olympic trials in 1956. He declined in order to pursue music.
John Royce "Johnny" Mathis (born September 30, 1935) is an American singer of popular music. Starting his career with singles of standards, he became highly popular as an album artist, with several dozen of his albums achieving gold or platinum status, and 73 making the Billboard charts.As confirmed by Guinnes World Book music chart historian Paul Gambacini " Johnny Mathis has sold over 350 Million records worldwide" Mathis was born in Gilmer, Texas, the fourth of seven children of Clem Mathis and his wife, Mildred Boyd. Their family moved to San Francisco, California, settling on 32nd Ave. in the Richmond District, where he grew up. His father had worked in vaudeville, and when he saw his son's talent, he bought an old upright piano for US$25 and encouraged his efforts. Mathis began learning songs and routines from his father; his first song being "My Blue Heaven." Mathis started singing and dancing for visitors at home, and at school and church functions.
Contributions by Evan1200, Drmagic, and Marcus2.


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#Flipped classroom streamed conference & some #history
Ignatia Webs
With all the changes that are happening in education (more online, more access for many students) the concept of the flipped classroom has gained a lot of attention, and it attracted a lot of researchers investigating its benefits and challenges. conferences education eLearning k12 online learning
WiZIQ offers free #iPad enabled online #classrooms for teachers
Ignatia Webs
Virtual classrooms are a technology in high demand as they allow any trainer or teacher to reach an international audience at any given moment. As such the educational department of the Institute of Tropical Medicine , who has students and partners around the world is taking a second look into the WiZIQ functionalities. seminar mobile virtual classroom wiziq ipad
New Book! "Cell Phones in the Classroom"
Cell Phones in Learning
My new book is coming out this September called Cell Phones in the Classroom: A Practical Guide for Educators ! First it has over 16 different cases of K-12 teachers integrating student's own cell phones into classroom learning. into classroom learning. Finally! It is once again being published by ISTE. I am very proud of this book. Their stories are inspiring!
Mobile Devices and the Flipped Classroom Model
The Mobile Learner
In the post, we will consider the use of mobile devices within the Flipped Classroom method. As I myself am currently learning about and thinking about the concept of the Flipped Classroom, it would be prudent to look elsewhere for a more definitive definition of the Flipped Classroom. In the Flipped Classroom model, the sequence is flipped.
Mobile Devices and the Flipped Classroom Model
The Mobile Learner
In the post, we will consider the use of mobile devices within the Flipped Classroom method. As I myself am currently learning about and thinking about the concept of the Flipped Classroom, it would be prudent to look elsewhere for a more definitive definition of the Flipped Classroom. For the purposes of this blog post, a simple description will do so simply put, a flipped classroom is a classroom where the instructional time and student activity time are reversed. In the Flipped Classroom model, the sequence is flipped.
#MOOC factors influencing teachers in formal #education
Ignatia Webs
This is a paper entitled MOOC factors influencing teachers in formal education was written for the Mexican open journal: Revista Mexicana de Bachillerato a distancia. gladly accepted the request, because I think MOOC can be used in multiple forms, supporting teachers in all areas of formal education. eLearning higher education k12 mooc online education online learning paper
Read the #mobile education report and join @gsma for #mlearning projects
Ignatia Webs
mobile network operators, handset manufacturers, systems and solutions providers) can offer to support education. GSMA is still looking for mobile education case studies and educational institutions which would be interested in working with mobile network operators on pilot projects. mobile mLearning education lifelong learning mobile learning informal learning
#MOOC disasters are human and part of educational innovation and why sandboxes are good
Ignatia Webs
With the Coursera course on the Fundamentals of Online Education: Planning and Application going down due to a mix of unfortunate events, sceptics of MOOC's feel strengthened. totally agree with her observation that institutions should stop thinking from what was (classroom teaching, teacher in front.) education collaborative learning mooc instructional design informal learning
Running race between open learning and formal higher education
Ignatia Webs
As the discussion on the future of higher education keeps on going, it is interesting to see how the presidents of colleges look upon these changes, particularly when looking at how top management looks at the pro's and con's of online learning. The public and college presidents differ over the educational value of online courses. Do Laptops and Smartphones Belong in the Classroom?
#IRRODL : Why the #chaos of #MOOC s and #mlearning will be a benefit to #education in the long run
Ignatia Webs
To all of us who think education is stressed for change, this paper on using mLearning and MOOCs to understand chaos, emergence, and complexity in education is a collaborative effort to embrace chaos in new educational formats (MOOC, mLearning) to come to a new educational balance. in the end. There are many other great articles in it. education2.0
New Book! "Cell Phones in the Classroom"
Cell Phones in Learning
My new book is coming out this September called Cell Phones in the Classroom: A Practical Guide for Educators ! First it has over 16 different cases of K-12 teachers integrating student's own cell phones into classroom learning. into classroom learning. Finally! It is once again being published by ISTE. I am very proud of this book. Their stories are inspiring!
#Teacher contest: using innovative practices in your classroom? Enter!
Ignatia Webs
My wonderful PAU education colleague Maria Perifanou just sent me a wonderful contest for all you primary and secondary teachers (in EU). The Open Education Europa portal has just launched a contest aiming at collecting and sharing innovative teaching practices taking place in Europe. From my end, I am going to ask my GUSCO colleagues to enter (one or three wonderful teachers working on the integrate MOOCs in secondary school classrooms to increase lifelong learning skills ). Inclusion; providing access to education or training to a previously excluded group or audience.
How to evaluate apps and websites for meeting your classroom needs
Cell Phones in Learning
However, once we are able to narrow down to a few options to use in their classroom, they need to do some evaluating of these sites for themselves. No site or app is perfect for all classrooms, so we need to make sure the resources they select are personalized well enough to suit their classroom needs. Thus it is important that we understand how to thoroughly evaluate the effectiveness of an app or resource to meet their classroom needs. Below are some of the criteria that we should be considering when bringing an app or website into their classroom for learning.
Emerging trends in education and mobile learning
Steve Vosloo
Overlapping of education trends and mobile-enabled opportunities. Why is this technological innovation different for education than previous moments (for example, the rise of television or the popularity of personal computers)? I don't believe that technology is the single driver of education transformation, although it is certainly a key influencing factor. Education is under pressure to change because of a number of factors. Recently, a United Nations task team led by UNESCO produced a think piece on education and skills beyond 2015 – key points listed below.
Flipped #eMOOCs2015 conference videos via EdX course
Ignatia Webs
Spreading the official words on the Flipped conference MOOC option: MOOCs are opening up new opportunities for faculty members to flip their classrooms. Can we apply this educational innovation to scientific conferences by flipping the conference room? conference eLearning flipped classroom mooc online learningEMOOCs 2015 is not only a flip mode conference but also an open one!
CIDER session: supporting online Teachers: Moving Pedagogical Know-How into Virtual Classrooms
Ignatia Webs
virtual classroom for instance does not immediately translate to a more open, pedagogically sound teaching, on more then one occasion virtual classrooms have resulted in ex-cathedra lessons, where the only benefit for the learner is that you do not get caught sleeping. It is an exploration of an action research project focusing on Master of Education professors working in conjunction with an instructional designer. pedagogy virtual classroom CIDER changeTechnology does not necessarily result in better teaching. in public! Francis Xavier University, Nova Scotia.
How to Integrate Mobile Technologies Into the Classroom
Float Mobile Learning
Mobile expert and author Chad Udell shares his experience speaking to an international audience on how to use mobile technologies in the classroom. Conferences Mobile Apps Pedagogy and Learning education Green Team
Higher Education and the Mobile Revolution: How Texts Make Better Schools and Students
Mobile Commons
Ten years ago, text messaging's role in the classroom was a head scratcher. All of these methods have helped keep classrooms full at a time when college admissions have dropped for the first time in 15 years. College enrollment, grade improvements, and staying connected with student services are just a few of the advantages of higher education texting. Write a letter?
iPad 2: whats in it for education?
uLearning Blog
Despite being a consumer device, it has seen massive adoption by professionals in business, medicine, and education. Here are the top 3 things that iPad 2 has going for it as far as education is concerned: 1. So what does the iPad not have yet for education? We also need clarity around education use off apps and iTunes content.
Launch of the Really Useful #EdTechBook #elearning enthusiasts
Ignatia Webs
This book has took only 6 months to gather 16 educational technologists, and all-round eLearning practitioners (both in online education, mobile learning, and any sub-section in technology enhanced learning). books ebook education eLearning online education online learning technology So what is the book about? Price Paperback: $29.99 / £19.99 / €24.99
Future of #mLearning inspiring ideas @dave_parsons
Ignatia Webs
However, once again to regard the mobile device as only for use at a distance is to miss its opportunities for use in the classroom, where mobile applications can support learning processes. education future future of education mLearning mobile mobile learning Imagine a future world where mobile learning is intuitive. What a refreshing research document! from mLearning.
free BJET issue on #MOOC disrupting teaching & learning in #HigherEd
Ignatia Webs
The British Journal of Educational Technologies just published a Special Issue: Massive Open Online Courses (MOOCs): 'disrupting' teaching and learning practices in higher education. Here is the short list of article titles, with a multitude of interesting MOOC angles: assessment, engagement, methods, improving classroom instruction. Lozano and Víctor M. R.
Engineering Intelligent Content for Mobile Learning by Rick Wilson & Gary Woodill : Learning Solutions Magazine
Mobile Learning Edge
Consider the possibilities open to teaching and engaging students when you take away the restrictions of a classroom-style format, allowing them to learn at a pace and in an environment that suits them … Once we add the ability to move around and to contextualize learning based on the learners location, the classroom metaphor barely works at all. Articles Industry Learning Theories Presentations classroom curriculum Gary Woodill Intelligent content mlearning Rick Wilson
The iPad mini review for Educators
uLearning Blog
WHAT ABOUT EDUCATION? Apple CEO Tim Cook reported during the iPad mini launch that 2500 US classrooms are now using iPads. In Australia the Sydney Morning Herald (1.7.12) has reported that 60% of Catholic Schools in the Sydney area have deployed them, with large official trials having been run by almost every state Education Department as well.
#oeb14 Ola Rosling with a #flipped keynote approach
Ignatia Webs
He merges his previously acquired knowledge from google, and is now taking it to education. conference flipped classroom OEB These are the notes I took during Ola Rosling''s keynote at Online Educa Berlin. Yesterday Ola Rosling made a very important remark on Big data and power, as big data is in the hands of the few, that same data is under the power influence of that few.
Free pdf eBook: theory & practice of #online teaching and learning
Ignatia Webs
The eBook has 6 chapters that are taken from other Routledge books mentioned at the beginning of this eBook: Chapter 1: the basics: This chapter takes on some basic but important questions about online teaching: how is it different from teaching in a traditional classroom environment? By including open resources in educational experiences, opportunities for learning increase dramatically.
Embracing Mobile To Educate For Tomorrow | MobileBehavior
mlearnopedia delicious
Mobile Behavior: an Omnicom Group Company Home People Blog Work Events Press About Us May 12, 2010 by Caleb Embracing Mobile To Educate For Tomorrow The classroom was traditionally a controlled environment; when wireless technology began to invade, skewing the rules of time and space, teachers panicked. We have been using smartphones in the classroom. Lets educate accordingly.
Hopes for #Google #MOOC partnership with #EdX
Ignatia Webs
With a bit of a delay some thoughts on Google''s move towards education ( lining up with EdX for the MOOC.org platform ). It does not come as too much of a surprise, as Google has been exploring education for a longer period of time. The Google teacher academy ignited new interest in using open tools for educational purposes. But in the end, teaching is a real craft.
iPods in the Classroom
mLearnopedia on Blogspot
Just discovered a publication with lots of good information and suggestions for using iPods in the classroom. Tags: resources education apps mobile learning iPod podcast article Enjoy! Open publication - Free publishing - More technology.
Free booklet on #Teaching with #Technology
Ignatia Webs
The booklet starts off with some figures regarding educational change: 98% of college & university presidents think that change is needed in education a and 67% think the change needs to be disruptive (Chronicle of Higher Ed study from 2014). connecting college classrooms from Morocco, Pakistan, US). education education2.0 higher education LMS report technology
Mobile Apps for Classroom Management and Assessment
Cell Phones in Learning
One area of education technology that we do not focus on enough is the ability for technology to aid teachers in assessing and tracking management in the classroom. The image that you work from is a seating chart for your classroom, and each student''s image or an avatar represents them. Below I will review a few of the FREE options I have come to appreciate.
Free 86 page book on Visible Learning via Routledge #visibleLearning
Ignatia Webs
Visible Learning The term visible learning (launched by John Hattie) is still gaining momentum and although its main focus is on classroom settings, with some adjustments you can use it across the educational board, including some online learning options. education educational methodology eLearning higher education k12 learner analytics learningwonder why?
great paid eBook on #mLearning field work
Ignatia Webs
This book should be useful for anyone teaching in the humanities that wants to extend learning beyond the classroom walls; it is also most useful for learners in these disciplines that want to extend their engagement with their subjects to their neighborhoods, their streets, and their cities. mobile mLearning education research mobile learning books ebook eLearning
True History of #MOOC with mixed panel by Steve Hargadon
Ignatia Webs
Steve Hargadon is famous for his Future of Education series in which he focuses on a number of educational changes and evolutions. He does this by interviewing a variety of educators, researchers and enthusiasts. The panel consisted of Dave Cormier is an educational activist, researcher, online community advocate and the Manager of Web Communications and Innovations at the University of Prince Edward Island. He has published on open education, Rhizomatic Learning, MOOCs (Massive Open Online Courses), Digital Identity, and practical classroom uses of virtual worlds.
Free Informal language & MOOC conference call #CfP #MOOC #Language
Ignatia Webs
Topics included but not limited to: · - MOOCs - design, learning, teaching, quality assurance, etc · - CALL and its normalisation · - Mobile-assisted language teaching and learning · - Informal language learning · - Learning to learn languages ● Student mobility ● Virtual classrooms, eLearning, and ePortfolio Confirmed keynote speakers are: Professor Agnes.Kukulska-Hulme (The Open University, UK) Dr Jeremy Knox (Edinburgh University, UK) Registration: Download the registration form from here. Deadline for submitting : 27 May 2016. Notification of acceptance : 10 June 2016.
5 Views of the Future of Mobile Learning
Mobile Learning Edge
James Clay's presentation is all visuals, but takes us from the history of farming, through the development of classrooms, to the future based on augmented reality. Visions about the Future of Mobile Learning | Educational Technology – Theory and Practice | Timo Ilomaki | 12 September 2011 Some are clearly pushing the envelope more than others.
Learning Mobile App Review: NearPod [Podcast Interview]
mLearning Revolution
There's no denying there's a revolution happening today in Education driven by important trends such as the Flipped Classroom, Bring Your Own Device (BYOD) and of course schools embracing mobile technologies creatively for learning. There are many great Apps out there from companies who are disrupting Learning and Education in a positive way through the use of Technology.
Call for papers: mobile and online learning #CfP
Ignatia Webs
high-impact, grass-roots training conference for classroom teachers by classroom teachers. This growth and attention has to do with the fact that Learning Analytics has become a multidisciplinary area where computer scientists, learning researchers, educational managers and practitioners can all cohabit. Important dates: Proposals need to be submitted by 30 January 2016. 2007).
Making Learning #data public from @CarnegieMellon
Ignatia Webs
Wonderful article from Inside Higher Ed mentioned that "Carnegie Mellon University will open the world's largest database on student learning to the public in an effort to identify best practices and standards for using technology in the classroom". It is just the way they move forward and the attempt they constantly make at using education to lift everyone up. Really nice.
Liveblog #emoocs2015 Amdocs a corporate training MOOC
Ignatia Webs
The content was always meaningful: no compromising in comparison to classroom content. The content was always meaningful: no compromising in comparison to classroom content. conferences corporate eLearning emoocs liveBlog mooc online education online learningThese moocs are seen as personal development, not mandatory training. 50% of the actual learners finished the course.


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DC9 Live at El Sibil, Ep. 1: Air Review
And if it's the YouTube you want, well, look no further.
We'll close out our pre-Thanksgiving day with a feast for the eyes and ears, straight from our kitchen to yours: episode one of our new weekly video series, DC9 Live at El Sibil.
Two weeks ago Pete mentioned that after 27 weeks of graciously hosting DC9 in SPACE, the closing of the Deep Ellum gallery left our weekly videos searching for a home. Last week, we found one -- and we're pretty excited about the possibilities the new location has to offer for future episodes.
After a Thanksgiving break, we'll be back on schedule, with free weekly shows in the Oak Cliff landmark known as "El Sibil." The big vine-covered house overlooking Lake Cliff, and the Dallas skyline beyond it, is the onetime home/studio built 80 years ago by frontier artist Frank Reaugh. A fire destroyed the house years later, right on down to the walk-in vault from which "El Sibil" takes its name. We're looking forward to continuing our weekly video series at El Sibil, with some help and hospitality from its current occupant, photographer/filmmaker Jason Whitbeck.
Upcoming Events
Andrea Bocelli
TicketsSat., Dec. 10, 8:00pm
E.Z. MO Breezy Presents...Grits & Biscuits
TicketsSat., Dec. 10, 9:00pm
World Famous Gospel Brunch
TicketsSun., Dec. 11, 10:30am
The Brian Setzer 13th Annual Christmas Rocks! Tour
TicketsSun., Dec. 11, 6:00pm
Kelsea Ballerini - The First Time Tour
TicketsTue., Dec. 13, 8:00pm
The local five-piece outfit Air Review joined us last week, along with a couple dozen of the band's friends, for a mellowed-out selection of cuts from their debut Landmarks. Along with a free mp3 from the band back in August, Pete mentioned the "impressive instrumental chops and a serious, impressive knack for vocal harmony" evident in the album -- check out the video above to hear for yourself. Along with Air Review's performance, you'll hear their thoughts on recording an album before playing live shows, and some fond memories from the band's earliest days.
We're off tonight for the Thanksgiving holiday, but here's hoping you can join us next Wednesday night for episode two of our new series, live at El Sibil.
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I am so tired I forgot my hard drive at home and I had to finish my homework until i don't know and I still have to read. What a day!
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|Property type
Property details
4-room house. Practical and cosy furnishings: entrance hall with separate WC. Dining room with dining table, radio and gas heater. Living room with TV, hi-fi system, DVD and gas heater. Kitchen (4 hot plates, oven, microwave, electric coffee machine) with small dining table. Shower. Upper floor: (steep stair), 2 rooms, each room with 2 beds. Interconnecting room with 1 bed. Terrace 18 m2, south facing position. Terrace furniture. Facilities: children's high chair, baby cot. The stairs to the upper floor is steep and tight. This house is therefore not suitable for people who have difficulty walking. There is no heating on the upper floor.
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Biggekerke 9 km from Middelburg: Small, simple, historical house De Tollenaer, from the 19th century. On the outskirts Biggekerke, 2.5 km from the sea, 2.5 km from the beach. In the house: storage room for bicycles, washing machine. Parking at the house. Supermarket 1.3 km, bakery, café 500 m, sandy beach Valkenisse 2.5 km. Golf course (9 hole) 13 km, minigolf 13 km. Nearby attractions: Neeltje Jans Deltawerken 28 km, Zeeuws Museum 9 km, Vlissingen 8 km, Middelburg 9 km.


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Apartment Features
- Air Conditioning
- Cable Ready
- Dishwasher
- Microwave
- Some Paid Utilities
- View
- Refrigerator
Special Features
- Pets
Community Features
- Accepts Electronic Payments
- Emergency Maintenance
- High Speed Internet Access
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- Trail, Bike, Hike, Jog
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Additional Features
- Air Conditioner
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- Pets Accepted Some Restrictions Apply Pets Accepted
Floor Plans & Pricing
Prices and availability subject to change without notice.
Property Details
Orange Development, Inc.
Orange Development Inc features one and two bedroom apartments in Duncannon, PA. Apartments feature private entrances, off-street parking, and modern appliances. Surrounded by the view of the Appalachian Mountain Range, the community is within walking distance to many town conveniences. Management and 24-hour emergency maintenance are provided by Property Management, Inc. Call us for a tour!
Lease Terms
Office Hours
Open Today
Apartments shown by Appointment
|Apartments shown by Appointment
|8:00 AM ~ 5:00 PM - Apartments shown by Appointment
|8:00 AM ~ 5:00 PM - Apartments shown by Appointment
|8:00 AM ~ 5:00 PM - Apartments shown by Appointment
|8:00 AM ~ 5:00 PM - Apartments shown by Appointment
|8:00 AM ~ 5:00 PM - Apartments shown by Appointment
|Apartments shown by Appointment
General Directions
Please call for directions.
Helpful Information
Fax: 7176357347
Visit the property's management website
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See other Property Management, Inc. Properties in your area.


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decided: December 12, 1968.
COMMONWEALTH EX REL. MASONv.MASON, APPELLANT
Appeal from order of Court of Common Pleas of Allegheny County, July T., 1968, No. 2166, in case of Commonwealth ex rel. Billy C. Mason v. Veronica Mason, now Veronica Shevchik.
Richard G. Zeleznik, for appellant.
William Moldovan, for appellee.
Wright, P. J., Watkins, Montgomery, Jacobs, Hoffman, Spaulding, and Hannum, JJ. Opinion by Montgomery, J.
[ 213 Pa. Super. Page 434]
In this habeas corpus proceeding relator, Billy C. Mason, the father of Linda Gale Mason, age eight, and Billy Clarence Mason, age five, sought to secure their custody from their mother, Veronica Shevchik, who resided with them in the Glassport-McKeesport area of Allegheny County, Pennsylvania.
These parents had been divorced by decree entered on April 28, 1966 by the Circuit Court of Alabama where the parties then resided. As a part of that decree there was included a provision that custody of the two children should vest in the mother with suitable
[ 213 Pa. Super. Page 435]
visitation rights given to the father. This arrangement had been agreed to by the parties. Thereafter, on March 25, 1967 the father remarried and later moved to Mississippi. The mother remarried on October 6, 1967 and with her husband and children moved to Allegheny County, Pennsylvania in January, 1968. This removal of the children from Alabama was contrary to the decree which provided that they should not be removed from the jurisdiction of the Alabama Court without first obtaining its express permission.
Following the removal of the children from Alabama their father advised the Alabama Court and petitioned the Court to modify its prior order. A copy of the petition was served on the mother by registered mail sent to her in McKeesport, Pennsylvania, which included a notice of a hearing to be held in Alabama on February 19, 1968. She did not respond to this notice which was received by her on February 12, 1968, and she did not appear at the hearing. The hearing, ex parte, resulted in a modification of the original decree and the granting of temporary custody to the father. A further hearing on the matter was set for March 1, 1968. On March 1, 1968 the mother again failing to appear at the hearing, the Court again granted temporary custody of the children to the father, suspended an order it had previously imposed on the father for the support of the children, and held the mother in contempt for removing them from the jurisdiction of that Court and refusing to appear with them at the aforestated hearings.
Thereafter, in May, 1968 the father instituted these proceedings in Allegheny County, and after hearing was awarded full custody of the children, ". . . until such time as the respondent, Veronica Mason, presents her petition to the Court in Alabama for a change of the custody order which as it now stands in Alabama awards full custody to the father."
[ 213 Pa. Super. Page 436]
This appeal followed the entry of that order. A petition for a supersedeas to prevent the immediate transfer of the children from the mother to the father was subsequently presented, but it was refused on condition that the father would post a surety bond in the sum of $1,000 to assure the presence of the children in Allegheny County, Pennsylvania when required. The bond was provided and the children were subsequently delivered to the father with whom they presently reside.
It appears clear to us that the learned lower court, in deciding this issue, erroneously placed too much reliance on the modified decree of the Alabama Court which was entered not because the welfare of the children required it, but because that Court had felt that the mother had contemptuously violated its order that the children be not removed from its jurisdiction without its express consent. Although we appreciate the feelings of that Court in this regard, we have repeatedly held that such orders are temporary, and that the courts of the jurisdictions where children presently reside must recognize their jurisdiction acquired by the presence of the children, and their duty to decide these cases on the basis of the present welfare of the children.
As has been repeatedly stated by our courts, the Commonwealth is vitally concerned with infants within its boundaries and an interested party in all matters affecting them. Ciammaichella Appeal, 369 Pa. 278, 85 A.2d 406 (1952); Commonwealth ex rel. Thomas v. Gillard, 203 Pa. Superior Ct. 95, 198 A.2d 377 (1964). Therefore we have not felt bound to enforce, without question, foreign decrees of this type.
To show the extent to which we have gone in applying this principle, reference is made to Irizarry Appeal, 195 Pa. Superior Ct. 104, 169 A.2d 307 (1961),
[ 213 Pa. Super. Page 437]
cert. denied, 368 U.S. 928, 82 S. Ct. 363, 7 L. Ed. 2d 191, in which case the writer of the present opinion dissented. Therein the children resided in Puerto Rico with their father to whom custody had been awarded by the courts of that jurisdiction. The mother and father had been lifelong residents of Puerto Rico and the children resided there during their entire lives except for annual visits to their mother, who had moved to Delaware County, Pennsylvania, following her divorce from the father. On the last visit of the children the mother detained them and petitioned the Delaware County Court for an award of custody after the children had been with her there only thirteen days. Jurisdiction was assumed and the court of that county awarded custody to the mother, which award was sustained.
We find no Pennsylvania authority recognizing the principle that the retention of jurisdiction over the children by the court making the initial award of custody or forbidding the removal of the children in any way alters the effect of their subsequent residence elsewhere, or preventing the courts of their present residence from assuming jurisdiction in such matters. The law in Pennsylvania is well settled that jurisdiction in custody cases follows either the domicile of the minor children or their residence, and the domicile of the children is that of the parent having custody. Irizarry Appeal, supra. See 23 Pitts. L. R. 465, 477-478 (1961).
While disregard of decrees of custody by sister states may lead to legalized abduction, and on general principles the enforcement of decrees of sister states would seem to be desirable, we have consistently held that the welfare of the child is the overriding consideration.
Unfortunately, in the present case, the lower court did not recognize that the welfare of these children
[ 213 Pa. Super. Page 438]
was the overriding consideration and relied too strongly on the Alabama Court's order. It did not pass on that point, saying, "I am not passing any judgment on her desirability as a parent of these children in the present circumstances."
Since we conclude that this matter must be remanded to the lower court for rehearing and reconsideration in the light of this opinion, we shall not engage in further discussion except to point out that these children are of tender years, were originally awarded to the mother with whom they had always lived, and had it not been for their removal from Alabama the mother would probably have continued to benefit by the original decree giving her custody. There appears no evidence that she had otherwise become unworthy of their care.
The order awarding the children to the father is overruled, the matter is remanded to the lower court for rehearing and further consideration; and the father is directed to forthwith return the children to the mother, who shall have custody of them until such time as the lower court shall hear and dispose of this matter as herein ordered.
Order reversed and case remanded.
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