Author: Larry Bernstein, MD
Creagh-BrownBC, Griffiths MJD, Evans TW. “Bench-to-bedside review: Inhaled nitric oxide therapy in adults”. Crit Care. 2009; 13(3): 221. Published online 2009 May 29. doi: 10.1186/cc7734. PMCID: PMC2717403.
This article is modified from a review series on Gaseous mediators, edited by Peter Radermacher. Other articles in the series can be found online athttp://ccforum.com/series/gaseous_mediators
Part I. Basic and downstream effects of inhaled NO
Inhaled nitric oxide (NO), a mediator of vascular tone produces pulmonary vasodilatation with low pulmonary vascular resistance. The route of administration delivers NO selectively improving oxygenation. Developments in our understanding of the cellular and molecular actions of NO may help to explain the results of randomised controlled trials of inhaled NO.
Introduction
Nitric oxide (NO), a determinant of local blood flow is formed by the action of NO synthase (NOS) on L-arginine in the presence of molecular oxygen. Inhaled NO results in preferential pulmonary vasodilatation it lowers pulmonary vascular resistance (PVR), correcting hypoxic pulmonary vasoconstriction (HPV). However, in the therapeutic use of gaseous NO to patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), and related conditions, evidence of a benefit is disappointing.
Administration of inhaled nitric oxide to adults
The licensed indication of inhaled NO is restricted to persistent pulmonary hypertension in neonates. Pharma-ceutical NO is costly, and raises concerns over potential adverse effects of NO. Therefore, an advisory board under the auspices of the European Society of Intensive Care Medicine and the European Association of Cardiothoracic Anaesthesiologists published recommendations in 2005 [1]. The sponsor had no authorship or editorial control over the content of the meetings or any subsequent publication.
The NO is administered as a NO/nitrogen mixture to the tubing of ventilated patients, and the NO and NO2 concen-trations are monitored, with methemoglobin levels measured regularly. Even though rapid withdrawal induces rebound pulmonary hypertension, it is avoided by gradual withdrawal [2]. There is variation in vasodilatory response to administered NO between patients [2] and in the same patient, and there is a leftward shift in the dose-response curve with use. Toxicity and loss of the therapeutic effect is a risk of excessive NO administration [3]. A survey of 54 intensive care units in the UK as well as results of a European survey revealed that the most common usage was in treating ARDS, followed by pulmonary hypertension [4], [5]. The only use of therapeutic inhaled NO usage in US adult patients reported from a single medical site (2000 to 2003) reveals that the most common application was in the treatment of RVF in patients after cardiac surgery and then, in surgical and medical patients for refractory hypoxemia[6].
Inhaled nitric oxide in acute lung injury and acute respiratory distress syndrome
ALI and ARDS are characterised by hypoxemia despite high inspired oxygen (PaO2/FiO2 [arterial partial pressure of oxygen/fraction of inspired oxygen] ratios of less than 300 mm Hg [40 kPa] and less than 200 mm Hg [27 kPa], respectively) in the context of evidence of pulmonary edema, and the absence of left atrial hypertension suggestive of a cardiogenic mechanism [7]. Pathologically, there is alveolar inflammation and injury leading to increased pulmonary capillary permeability and a serous alveolar fluid with inflammatory infiltrate. This is manifest clinically as hypoxemia, inadequate alveolar perfusion, venous-arterial shunting, atelectasis, and reduced compliance.
Since 1993, when the first investigation on the effects of NO on adult patients with ARDS was published [8], there have been several randomised controlled trials (RCTs) examining the effect in ALI/ARDS (Table 1). The first systematic review and meta-analysis [9] found no beneficial effect on mortality or ventilator-free days. A more recent meta-analysis that considered 12 RCTs with a total of 1,237 patients [10] concluded: [1] no mortality benefit, [2] improved oxygenation at 24 hours (13% improvement in PaO2/FiO2 ratio) at the cost of increased risk of renal dysfunction (relative risk 1.50, 95% confidence interval 1.11 to 2.02). Based on a trend to increased mortality in patients receiving NO, the authors suggested that it not be used in ALI/ARDS. Why the NO fails to improve patient outcomes requires clarifying the effects of inhaled NO that occur outside the pulmonary vasculature.
From:
Studies of inhaled nitric oxide in adult patients with acute lung injury/acute respiratory distress syndrome
The biological action of inhaled nitric oxide
NO was first identified as an endothelium-derived growth factor (EDGF) and an important determinant of local blood flow [11]. NO reacts very rapidly with free radicals, certain amino acids, and transition metal ions. The action of NOS on the semi-essential amino acid L-arginine in the presence of molecular oxygen and its identity with EDGF was the basis for the Nobel discovery of Furthgott and others [12]. Three isoforms of NO are: neuronal NOS, inducible NOS (iNOS or NOS2), and endothelial NOS (eNOS or NOS3). Calcium-independent iNOS generates higher concentrations of NO [13] than the other isoforms and its role has been implicated in the pathogenesis septic shock.
Exogenous NO is administered by controlled inhalation or through intravenous administration of NO donors. It was thought to have no remote or non-pulmonary effects. The effect NO has on circulating targets is shown. (Figure 1).
From:
New paradigm of inhaled nitric oxide (NO) action. Figure 1 illustrates the interactions between inhaled NO and the contents of the pulmonary capillaries. Although NO was considered to be inactivated by hemoglobin (Hb), proteins including Hb and albumin contain reduced sulphur (thiol) groups that react reversibly with NO causing it to lose its vasodilating properties. A stable derivate, in the presence of oxyhemoglobin, is formed by a reaction resulting in nitrosylation of a cysteine residue of the β subunit of Hb. The binding of NO to the heme iron predominates in the deoxygenated state [14]. If circulating erythrocytes store and release NO peripherally in areas of low oxygen tension, this augments peripheral blood flow and oxygen delivery via decreased systemic vascular resistance [15]. Thus, NO can act as an autocrine or paracrine mediator but when stabilised may exert endocrine influences [16]. In addition to de novo synthesis, supposedly inert anions nitrate (NO3–) and nitrite (NO2–) can be recycled to form NO, and nitrite might mediate extra-pulmonary effects of inhaled NO [17]. In the hypoxic state, NOS cannot produce NO and deoxy-hemoglobin catalyses NO release from nitrite, potentially providing a hypoxia-specific vasodilatory effect. Given that effects of inhaled NO are mediated in part by S-nitrolysation of circulating proteins, therapies aiming at directly increasing S-nitrosothiols have been developed.
Introduce another effect. When inhaled with high concentrations of oxygen, gaseous NO slowly forms the toxic product NO2, but other potential reactions include nitration (addition of NO2+), nitrosation (addition of NO+), or nitrosylation (addition of NO), and reaction with reactive oxygen species such as superoxide to form reactive nitrogen species (RNS) such as peroxynitrite (ONOO–). These reactions of NO, potentially cytotoxic NO2 , and covalent nitration of tyrosine in proteins by RNS lead to measures of oxidative stress.
In a small observational study, inhaled ethyl nitrite safely reduced PVR without systemic side effects in persistent pulmonary hypertension of the newborn [18]. In animal models, pulmonary vasodilatation was maximal in hypoxia and had prolonged duration of action after cessation of administration [19].
References
- Germann P, Braschi A, Della Rocca G, Dinh-Xuan AT, et al. Inhaled nitric oxide therapy in adults: European expert recommendations. Intensive Care Med. 2005;31:1029–1041. [PubMed]
- Griffiths MJ, Evans TW. Inhaled nitric oxide therapy in adults. N Engl J Med. 2005;353:2683–2695. [PubMed]
- Gerlach H, Keh D, Semmerow A, Busch T, et al. Dose-response characteristics during long-term inhalation of nitric oxide in patients with severe acute respiratory distress syndrome: a prospective, randomized, controlled study. Am J Respir Crit Care Med. 2003;167:1008–1015. [PubMed]
- Cuthbertson BH, Stott S, Webster NR. Use of inhaled nitric oxide in British intensive therapy units. Br J Anaesth. 1997;78:696–700.[PubMed]
- Beloucif S. A European survey of the use of inhaled nitric oxide in the ICU. Working Group on Inhaled NO in the ICU of the European Society of Intensive Care Medicine. Intensive Care Med. 1998;24:864–877.[PubMed]
- George I, Xydas S, Topkara VK, Ferdinando C, et al. Clinical indication for use and outcomes after inhaled nitric oxide therapy. Ann Thorac Surg. 2006;82:2161–2169. [PubMed]
- Bernard GR, Artigas A, Brigham KL, Carlet J,et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med. 1994;149:818–824. [PubMed]
- Rossaint R, Falke KJ, López F, Slama K, Pison U, Zapol WM. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med.1993;328:399–405. [PubMed]
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- Nitric Oxide: The Nobel Prize in Physiology or Medicine 1998 Robert F. Furchgott, Louis J. Ignarro, Ferid Murad. Leaders in Pharmacutical Intelligence. A blog specializing in Pharmaceutical Intelligence and Analytics
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- Moya MP, Gow AJ, Califf RM, Goldberg RN, Stamler JS. Inhaled ethyl nitrite gas for persistent pulmonary hypertension of the newborn. Lancet 2002; 360:141–143. [PubMed]
Creagh-BrownBC, Griffiths MJD, Evans TW. “Bench-to-bedside review: Inhaled nitric oxide therapy in adults”. Crit Care. 2009; 13(3): 221. Published online 2009 May 29. doi: 10.1186/cc7734. PMCID: PMC2717403.
This article is modified from a review series on Gaseous mediators, edited by Peter Radermacher.
Other articles in the series can be found online athttp://ccforum.com/series/gaseous_mediators
Part II. Application of inhaled NO and circulatory effects
Cardiovascular effects
NO activates soluble guanylyl cyclase by binding to its heme group to form cyclic guanosine 3’5′-monophosphate (cGMP) activating a protein kinase. Consequently, myosin sensitivity to calcium-induced contraction is reduced lowering the intracellular calcium concentration as a result of activating calcium-sensitive potassium channels and inhibiting release of calcium. The smooth muscle cell (SMC) relaxation with decrease in pulmonary vascular resistance (PVR) and decreased RV after load could improve cardiac output. However, left ventricular impairment associated with decrease in PVR allows increased RV output to a greater extent than the left ventricle can accommodate and the increase in left atrial pressure reinforces pulmonary edema.
Inhaled NO augments the normal physiological mechanism of hypoxic pulmonary ventilation (HPV) and improves systemic oxygenation (Figure 2). The effects of inhaled NO on systemic oxygenation are limited. Experiments show that intravenously administered vasodilators counteract HPV [3]. However, the non-pulmonary effects of inhaled NO include increased renal and hepatic blood flow and oxygenation [14].
From:
Hypoxic pulmonary vasoconstriction (HPV). (a) Normal ventilation-perfusion (VQ) matching. (b) HPV results in VQ matching despite variations in ventilation and gas exchange between lung units. (c) Inhaled nitric oxide (NO) augmenting VQ matching by vasodilating.
Non-cardiovascular effects relevant to lung injury
Neutrophils are important cellular mediators of ALI. Limiting neutrophil production of oxidative species and proteolysis reduces lung injury. In neonates, prolonged administration of NO diminished neutrophil-mediated oxidative stress [19]. Neutrophil deformability and CD18 expression were reduced in animal models [20] accomp-anied by decreases in adhesion and migration [21]. These changes limit damage to the alveolar-capillary membrane and the accumulation of protein-rich fluid within the alveoli. Platelet activation and aggregation, intra-alveolar thrombi, contribute to ALI. Inhaled NO attenuates the procoagulant activity in animal models of ALI [22] and a similar effect is seen in patients with ALI [23], but also in healthy volunteers [23,24]. In patients with ALI, decreased surfactant activity in the alveoli and noncompliance, as we recall is hyaline membrane disease accompanied by impaired pulmonary function [25]. The deleterious effects of the NO damages the alveolar wall with loss of surfactant by reactions with RNS [26]. Finally, prolonged exposure to NO in experimental models impairs cellular respiration [27].
The failure of inhaled NO to improve outcome in ALI/ARDS is therefore potentially due to several factors. First, patients with ALI/ARDS die of multi-organ failure, as the actions of NO are not expected to improve the outcome of multi-organ failure, which is a cytokine driven process leading to circulatory collapse. Indeed, the expected beneficial effect of inhaled NO is abrogated by detrimental downstream systemic effects discussed. Second, ALI/ARDS is a heterogeneous condition with diverse causes. Finally, using inhaled NO without frequent dose titration risks unwanted systemic effects without the expected benefits.
Other clinical uses of inhaled nitric oxide
Pulmonary hypertension and acute right ventricular failure
RVF may develop when there is abnormally elevated PVR and/or impaired RV perfusion. Table 2 lists common causes of acute RVF. The RV responds poorly to inotropic agents but is exquisitely sensitive to after load reduction.
From:
Reducing PVR will have beneficial effects on cardiac output and therefore oxygen delivery. In the context of high RV afterload with low systemic pressures or when there is a limitation of flow within the right coronary artery [28], RV failure triggers a backward failure of venous return, as diagrammatically represented in Figure 3.
From:
Pathophysiology of right ventricular failure. CO, cardiac output; LV, left ventricle; PAP, pulmonary artery pressure; PVR, pulmonary vascular resistance; RV, right ventricle.
Inhaled NO is used when RV failure complicates cardiac surgery, as cardiopulmonary bypass per se causes diminished endogenous NO production [29]. There is marked variation in response to inhaled NO between patients [30] and in the same patient over time. After prolonged use, there is a leftward shift in the dose-response curve. The risk of excessive NO administration is associated with toxicity and loss of the therapeutic effect without regular titration against a therapeutic goal [31]. Further, cardiac transplantation may be complicated by pulmonary hypertension and RVF that are improved with NO [32]. Early ischemia-reperfusion injury after lung transplantation manifests clinically as pulmonary edema and is a cause of significant morbidity and mortality [33,34]. Although NO has been administered in this circumstance [35], it hasn’t prevented ischemia-reperfusion injury in clinical lung transplantation [36]. Inhaled NO has been used successfully in patients with cardiogenic shock and RVF associated with acute myocardial infarction [37,38,46], and in patients with acute RVF following acute pulmonary venous thrombo-emboli [39, 47]. An explanation is needed in view of the downstream effects of systemic vasoconstriction and MOF previously identified. No systematic evaluation of inhaled NO and its effect on clinical outcome has been conducted in these conditions.
Acute chest crises of sickle cell disease
Acute chest crises are the second most common cause of hospital admission in patients with sickle cell disease (SCD) and are responsible for 25% of all related deaths [40]. Acute chest crises are manifest by fever, respiratory symptoms or chest pain, and new pulmonary infiltrate on chest x-ray. The major contributory factors are related to vaso-occlusion. Hemolysis of sickled erythrocytes releasing Hb into the circulation generates reactive oxygen species and reacts with NO [41]. In SCD, the free Hb depletes NO. In addition arginase 1 is released, depleting the arginine needed for NO production, [42]. While secondary PVH is common in adults with SCD the physiological rationale for the use of inhaled NO needs to be considered, except for the complication just referred to. Thus far, iNO has failed to demonstrate either persistent improvements in physiology or beneficial effects on any accepted measure of outcome in clinical trials (other than its licensed indication in neonates). Therefore, inhaled NO is usually reserved for refractory hypoxemia.
Potential problems in designing and conducting RCTs in the efficacy of inhaled NO are numerous. Blinded trials will be difficult to conduct as the effects of inhaled NO are immediately apparent. Recruitment is limited as there is little time for consent/assent or randomization. Finally, industry funding might cast doubt on the independence of the trial results.
Inhaled NO is an unproved tool in the intensivist’s armamentarium of rescue therapies for refractory hypoxemia even though it has an established role in managing complications of cardiac surgery and in heart/lung transplantation. The current place for inhaled NO in the management of ALI/ARDS, acute sickle chest crisis, acute RV failure, and acute pulmonary embolism is a rescue therapy.
Abbreviations
ALI: acute lung injury; ARDS: acute respiratory distress syndrome; Hb: haemoglobin; HPV: hypoxic pulmonary vasoconstriction; iNO: inhaled nitric oxide; iNOS: inducible nitric oxide synthase; NO: nitric oxide; NO2: nitrogen dioxide; NOS: nitric oxide synthase; PaO2/FiO2: arterial partial pressure of oxygen/fraction of inspired oxygen; PVR: pulmonary vascular resistance; RCT: randomised controlled trial; RNS: reactive nitrogen species; RV: right ventricle; RVF: right ventricular failure; SCD: sickle cell disease; SMC: smooth muscle cell.
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- Gessler P, Nebe T, Birle A, Mueller W, Kachel W. A new side effect of inhaled nitric oxide in neonates and infants with pulmonary hypertension: functional impairment of the neutrophil respiratory burst. Intensive Care Med 1996; 22:252–258. [PubMed]
- Sato Y, Walley KR, Klut ME, English D, D’yachkova Y, et al. Nitric oxide reduces the sequestration of polymorphonuclear leukocytes in lung by changing deformability and CD18 expression. Am J Respir Crit Care Med 1999; 159:1469–1476. [PubMed]
- Bloomfield GL, Holloway S, Ridings PC, Fisher BJ, et al. Pretreatment with inhaled nitric oxide inhibits neutrophil migration and oxidative activity resulting in attenuated sepsis-induced acute lung injury. Crit Care Med 1997; 25:584–593. [PubMed]
- Kermarrec N, Zunic P, Beloucif S, Benessiano J, et al. Impact of inhaled nitric oxide on platelet aggregation and fibrinolysis in rats with endotoxic lung injury. Role of cyclic guanosine 5′-monophosphate. Am J Respir Crit Care Med. 1998;158:833–839.[PubMed]
- Gries A, Bode C, Peter K, Herr A, Böhrer H, et al. Inhaled nitric oxide inhibits human platelet aggregation, P-selectin expression, and fibrinogen binding in vitro and in vivo. Circulation. 1998;97:1481–1487. [PubMed]
- Gries A, Herr A, Motsch J, Holzmann A, Weimann J, et al. Randomized, placebo-controlled, blinded and cross-matched study on the antiplatelet effect of inhaled nitric oxide in healthy volunteers. Thromb Hemost 2000; 83:309–315. [PubMed]
- Cheng IW, Ware LB, Greene KE, Nuckton TJ, et al. Prognostic value of surfactant proteins A and D in patients with acute lung injury. Crit Care Med 2003; 31:20–27. [PubMed]
- Robbins CG, Davis JM, Merritt TA, Amirkhanian JD et al. Combined effects of nitric oxide and hyperoxia on surfactant function and pulmonary inflammation. Am J Physiol 1995; 269(4 Pt 1):L545–550. [PubMed]
- Clementi E, Brown GC, Feelisch M, Moncada S. Persistent inhibition of cell respiration by nitric oxide: crucial role of S-nitro-sylation of mitochondrial complex I and protective action of glutathione. Proc Natl Acad Sci USA 1998; 95:7631–7636. [PMC free article] [PubMed]
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- Ardehali A, Hughes K, Sadeghi A, Esmailian F, et al. Inhaled nitric oxide for pulmonary hypertension after heart transplantation. Transplantation 2001; 72:638–641. [PubMed]
- King RC, Binns OA, Rodriguez F, Kanithanon RC, et al. Reperfusion injury significantly impacts clinical outcome after pulmonary transplantation. Ann Thorac Surg 2000; 69:1681–1685. [PubMed]
- de Perrot M, Liu M, Waddell TK, Keshavjee S. Ischemia-reperfusion-induced lung injury. Am J Respir Crit Care Med 2003; 167:490–511. [PubMed]
- Kemming GI, Merkel MJ, Schallerer A, Habler OP, et al. Inhaled nitric oxide (NO) for the treatment of early allograft failure after lung transplantation. Munich Lung Transplant Group. Intensive Care Med 1998; 24:1173–1180. [PubMed]
- Meade MO, Granton JT, Matte-Martyn A, McRae K, aet al. Toronto Lung Transplant Program A randomized trial of inhaled nitric oxide to prevent ischemia-reperfusion injury after lung transplantation. Am J Respir Crit Care Med 2003; 167:1483–1489.[PubMed]
- Fujita Y, Nishida O, Sobue K, Ito H, et al. Nitric oxide inhalation is useful in the management of right ventricular failure caused by myocardial infarction. Crit Care Med 2002; 30:1379–1381. [PubMed]
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Dr. Larry,
Thank you for the outstanding post of NO inhaler and Pulmonary and cardiac disease.
GREAT post and important overview of the physiology of the cardiopulmonary compensatory mechanism.
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PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
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I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette