Within the past two decades, interest in understanding the therapeutic mechanisms of ketogenic diet (KD) action has grown steadily. Expanded knowledge about underlying mechanisms has yielded insights into the biochemical basis of brain function, both normal and pathologic. Metabolic changes likely related to the KD’s anticonvulsant properties include – but are not limited to – ketosis, reduced glucose, elevated fatty acid levels, and enhanced bioenergetic reserves. Direct neuronal effects induced by the KD may involve ATP-sensitive potassium (K_ATP) channel modulation, enhanced purinergic (i.e., adenosine) and GABAergic neurotransmission, increased brain-derived neurotrophic factor (BDNF) expression consequent to glycolytic restriction, attenuation of neuroinflammation, as well as an expansion in bioenergetic reserves and stabilization of the neuronal membrane potential through improved mitochondrial function. Importantly, beyond its utility as an anticonvulsant treatment, the KD may also exert neuroprotective and anti-epileptogenic properties, heightening the clinical potential of the KD as a disease-modifying intervention. As dietary treatments are already known to evoke a wide array of complex metabolic changes, future research will undoubtedly reveal a more complex mechanistic framework for KD action, but one which should enable improved formulations offering comparable or superior efficacy with fewer side-effects, not only for epilepsy but perhaps a broader range of neurological disorders.

INTRODUCTION

The ketogenic diet (KD) is a high-fat, low-carbohydrate, adequate protein diet that has been employed as a treatment for medically-refractory epilepsy for over 90 years.¹ This “alternative” therapy was originally designed to mimic the biochemical changes associated with fasting, a treatment reported anecdotally over millennia to control seizure activity. The hallmark features of KD treatment are the production of ketone bodies (principally β-hydroxybutyrate, acetoacetate and acetone) – products of fatty acid oxidation in the liver – and reduced blood glucose levels (Figure 1). Ketone bodies provide an alternative substrate to glucose for energy utilization, and, in the developing brain, also constitute essential building blocks for the biosynthesis of cell membranes and lipids.

Figure 1

Metabolic pathways involved in ketogenic diet (KD) treatment. In the liver, fatty acids are ordinarily converted into acetyl-CoA which enters the tricarboxylic acid (TCA) cycle. When fatty acid levels are elevated and exceed the metabolic capacity of (more...)

Throughout much of the past century, the popularity of the KD has waxed and waned. Initial enthusiasm was fueled by dramatic success rates, reported entirely in uncontrolled studies, but was quickly supplanted by new antiepileptic drugs (such as phenytoin) that became available in the 1930’s. Clinicians found it more convenient to administer a drug than supervise a regimen requiring scrupulous attention to foodstuffs and avoidance of anti-ketogenic carbohydrates. Notwithstanding the prolonged stigma of being a fad therapy and one without a credible scientific basis, the KD experienced a major resurgence in the late 1990’s, mostly as a consequence of serendipitous media attention and the continued failure of even newer antiepileptic drugs to offer significantly enhanced clinical efficacy.

Today, the KD is acknowledged as a proven therapy for epilepsy.² The growing number of clinical KD treatment centers throughout the world serves as a testament to the notion that irrespective of cultural and ethnic differences that define dietary and nutritional practices, a fundamental shift from carbohydrate-based consumption to fatty acid oxidation results in similar clinical effects. Despite such broad use, surprisingly little is understood about its underlying mechanisms of action. This may be due to the inherently complex interplay between the network dynamics of the human brain (particularly in the disease state and during development), and the myriad biochemical and physiological changes evoked by consumption of dietary substrates. It has not been straightforward to determine cause-and-effect relationships in this bewildering context, and one cannot be certain whether specific molecular and cellular alterations observed are relevant or simply represent epiphenomena. This knowledge gap has hindered efforts to develop improved or simplified treatments (such as a “KD in a pill”³) that obviate the strict adherence to protocol that the KD requires. However, research efforts have been intensifying over the past decade, and recent investigations have provided new insights and molecular targets.

Herein we outline the most prominent mechanisms underlying KD action. We introduce these mechanisms chronologically as they were proposed, integrate these ideas with more recent findings, and examine the evidence for the broad neuroprotective properties of the KD – the latter, if validated, would highlight the clinical potential of the KD as a broadly encompassing disease-modifying intervention.^4–7 Whether the cellular mechanisms responsible for the clinical utility of the KD for human epilepsies are identical to those observed in animal models, or whether they overlap with the mechanisms that afford clinical benefits for other neurological conditions, remains to be determined. An integration of older and newer ideas regarding underlying mechanisms of KDs might represent the ideal scientific strategy to eventually unlock the secrets of this metabolism-based therapy.

HISTORICAL AND CLINICAL PERSPECTIVES

Clinical Insights

From decades of clinical experience, it is been observed that almost any diet resulting in ketonemia and/or reduced blood glucose levels can produce an anticonvulsant effect. Comparable clinical efficacy has been seen using KDs comprised of either long-chain triglycerides (LCTs)^20,21 or medium-chain triglycerides (MCTs).^22–25 Within the last decade, two additional variations of these KDs have emerged²⁶: the modified Atkin’s diet (MAD)^27–30 and the low-glycemic index treatment (LGIT).^31–33 The former allows for more liberal carbohydrate consumption and does not significantly restrict protein intake compared to the classic KD, whereas the latter was developed to mirror reduced glucose levels during KD treatment, and as such is based on a fundamental adherence to foods with low glycemic indices. The glycemic index is a value that describes the extent to which a carbohydrate is absorbed and elevates blood glucose, and lower indices correlate with slower insulin responses compared to glucose. Interestingly, LGIT does not induce the prominent ketosis seen with classic KDs and the Atkin’s diet.

Thus, at present, there are three primary dietary therapies for epilepsy: the traditional KD (a variation of which is the MCT diet), the MAD, and the LGIT. All three diets have been increasingly studied and are being used currently for both children and adults in centers worldwide. Importantly, available evidence indicates that dietary composition per se does not appear to affect the anticonvulsant efficacy of the diet, as long as there is a degree of sustained ketosis and/or calorie restriction.^34–39 And, although there are patients with epilepsy who respond dramatically within days of initiating the KD, maximum efficacy is not generally achieved for several days or weeks after initiation, suggesting that longer-term adaptive metabolic and/or genetic mechanisms may be recruited.⁴⁰ These adaptations are likely generalized throughout the epileptic brain, irrespective of underlying pathology or genetic predisposition to seizures, because the KD is an effective treatment for diverse epileptic conditions.^41,42 Table 1 provides a general context for the subsequent discussion, comparing and contrasting key parameters observed clinically and in experimental models.

TABLE 1

Ketogenic Diet: Clinical Correlates and Experimental Observations.

ANIMAL MODELS

MECHANISTIC STUDIES IN THE EARLY RENAISSANCE ERA

Ultimately, to produce anticonvulsant effects, the KD must reduce neuronal excitability and/or synchony. The essential currency of neuronal excitability – both normal and aberrant – is the complex array of primarily voltage-gated and ligand-gated ion channels that determine the firing properties of neurons and mediate synaptic transmission. At present, there appears to be at least six important mechanisms through which the currently available antiepileptic drugs exert their anticonvulsant action,^72–74 and the vast majority of molecular targets are ion channels and transporters localized to plasmalemmal membranes. In this light, a fundamental question pertaining to KD effects at the cellular and molecular levels has been whether any of the metabolic substrates (e.g., ketone bodies) elaborated by this “non-pharmacological” intervention can interact with ion channels known to regulate neuronal excitability. Broadly speaking, this does not appear to be the case. Given this tantalizing situation, there has been intense recent interest in how metabolic changes induced by a KD translate in a causal manner to a reduction in neuronal excitability and/or synchrony. Most of the postulated mechanisms discussed below are considered in the context of multiple lines of evidence, from human data as well as in vivo and in vitro model systems.

GABAergic Inhibition

An enduring hypothesis regarding the mechanisms KD action involves enhancement of GABA-mediated inhibition. Facilitation of GABAergic neurotransmission has long been accepted as a critical mechanism of action for a variety of clinically effective antiepileptic drugs, and thus there is an intrinsic appeal to invoking this mechanism. With respect to ketone bodies, however, GABA_A receptors do not appear to be the primary targets in this regard. The indirect evidence comes from acute animal studies in which the KD is found to be most effective against seizures evoked by the GABAergic antagonists (i.e., PTZ, bicuculline, picrotoxin and γ-butyrolactone), whereas it fails to block acute seizures provoked by kainic acid, strychnine (a glycine receptor antagonist), and maximal electroshock (MES; involving voltage-dependent sodium channels).⁴⁸

More direct evidence comes from electrophysiological recordings conducted in vivo, demonstrating that the KD increased paired-pulse inhibition and elevated maximal dentate activation threshold in rats, consistent with an elevated seizure threshold via enhancement of GABAergic inhibition.³⁷ In a related study, caloric restriction - which results in mild ketosis - enhanced the expression of both isoforms of glutamic acid decarboxylase (GAD65 and GAD67, the biosynthetic enzymes for GABA) in the tectum, cerebellum, and temporal cortex of rats, suggesting increased GABA levels.¹¹⁰ However, increased GAD expression might actually reflect decreased GABA production^111–113 so the ramifications of these findings to neuronal inhibition remain unclear.

At a neurochemical level, Yudkoff and colleagues have proposed that in the ketotic state, a major shift in brain amino acid handling results in a reduction of aspartate relative to glutamate (the precursor to GABA synthesis), and a shift in the equilibrium of the aspartate amino-transferase reaction.^114–117 This adaptation in the metabolism of the excitatory neurotransmitter glutamate (i.e., a decrease in the rate of glutamate transamination to aspartate) would be predicted to increase the rate of glutamate decarboxylation to GABA, the major inhibitory neurotransmitter, because more glutamate would be available for the synthesis of both GABA and glutamine.^114,115,118 An increase in brain GABA levels would then be expected to dampen seizure activity (Figure 2). But is there any evidence that the KD increases GABA levels in seizure-prone areas of the brain? The experimental data thus far are inconsistent or are reflective of changes outside of critical areas such as the hippocampus, thalamus and neocortex.^{10,91,114,119} Two clinical studies have reported significant increases in GABA levels following KD treatment,^120,121 however, further substantiating this view. More recent work has demonstrated that BHB decreases GABA degradation, and thus could increase the available pool of GABA.¹²² Collectively, whereas both laboratory and clinical data support a role for increases in GABA levels and presumably increased inhibition via GABA receptors as a potential mechanism underlying KD action, it remains unclear why a KD can be effective in stopping seizures in patients who have failed to respond to GABAergic drugs.

Figure 2

The metabolic inter-relationships between brain metabolism of glutamate, ketone bodies and glucose. In ketosis, 3-OH-butyrate (β-hydroxybutyrate) and acetoacetate contribute heavily to brain energy needs. A variable fraction of pyruvate (1) is (more...)

METABOLIC MECHANISMS

The earliest demonstration that the KD enhances energy substrates was provided by DeVivo and colleagues¹¹⁹ who showed significant increases in brain bioenergetic substrates such as ATP, creatine and phosphocreatine in normal adult rats fed a high-fat diet for three weeks. The metabolic data examined in this study indicated an overall increase in the cerebral energy reserve and energy charge which the authors believed could account for the neuronal stability that accompanied the chronic ketosis. A later study confirmed the elevation in brain adenine nucleotides as a consequence of KD treatment.¹⁵⁷ However, the most compelling demonstration that the KD profoundly affects energy metabolism was by Bough and colleagues who used microarray and electron microscopic techniques to examine patterns of gene expression in the hippocampus of rats fed either a KD or control diet.⁹¹ They quantified a robust up-regulation of transcripts encoding metabolism enzymes and mitochondrial proteins, and an increased number of mitochondrial profiles. Importantly, and consistent with increased energy reserves, hippocampal slices from KD-fed animals were highly resistant to the metabolic stress induced by low glucose conditions. Additional studies support the beneficial effects of a KD on mitochondrial energy metabolism.^64,158 Figure 3 highlights some of the effects of the KD on mitochondrial function.

Figure 3

Major changes in important biochemical pathways reported to exert anticonvulsant and anti-epileptogenic effects in experimental models (shadowed boxes; also see text). Below, Putative interactions between mitochondrial respiratory complexes (MRCs) and (more...)

As intriguing as these studies are, how exactly would enhanced energy reserves lead to a stabilization of synaptic functioning, membrane potential and diminished seizure activity? One interpretation of the neuronal consequences of these bioenergetic changes is that neurons are better able to maintain ionic gradients and resting membrane potential, and thus resist depolarizing influences. The most likely way this stabilization is accomplished is through the Na⁺/K⁺ ATPase pump; specifically, KD-induced elevations in ATP concentrations might enhance and/or prolong the activation of the Na⁺/K⁺-ATPase, perhaps via an increase in the delta-G′ of ATP hydrolysis.¹⁵⁹ To date, however, there are no published studies directly testing this sodium-pump hypothesis in epileptic brain.

There is an alternate and complementary hypothesis linking increased energy substrate availability with membrane hyperpolarization. Kawamura and colleagues evaluated the electrophysiological effects of reduced glucose (a consistent finding in patients successfully treated with the KD) in CA3 hippocampal pyramidal neurons – importantly, under conditions of adequate or enhanced ATP levels, but without the addition of ketone bodies – using whole-cell recording techniques.¹⁶⁰ These investigators found that glucose restriction led to ATP release through pannexin hemichannels localized on CA3 neurons. The increased extracellular ATP, upon rapid degradation by ectonucleotidases to adenosine, resulted in activation of adenosine A1 receptors which were shown to be coupled to opening of plasmalemmal K_ATP channels. This study highlights a novel mechanism of metabolic autocrine regulation, involving close cooperativity among pannexin hemichannels, adenosine receptors and K_ATP channels, and provides an elegant link to an earlier study demonstrating ketone-mediated attenuation of spontaneous neuronal discharge in SNr.⁷⁷ It should be noted that the potential contribution of adenosine is plausible, given the well-substantiated role of this endogenous purine in suppressing cellular excitability.¹⁶¹ Consistent with the involvement of adenosine, this latter group recently found evidence that the KD suppresses electrographic seizures in vivo in mice with spontaneous seizures, through a mechanism involving A1 receptors.¹⁶²

It is important to note that the observation that reduced glucose might contribute to seizure control is not recent. Calorie restriction in rodents was shown to reduce seizure susceptibility, and lowered levels of blood glucose correlated with inhibition of epileptogenesis in a genetic model.^35,163 When examining the interplay of glucose levels and ketosis, metabolic control theory would argue that glucose restriction might be more important than ketonemia.¹⁶⁴ Clinically, the link between blood glucose levels and seizure control has yet to be proven, and skepticism regarding relative hypoglycemia as the major contributor to KD action is supported by the incongruency of animal data.¹⁶⁵

Another potentially important consequence of reduced glucose has been highlighted through the use of 2-deoxy-D-glucose (2DG), a glucose analog that inhibits glycolysis by blocking phosphoglucose isomerase. 2DG has been shown to be a potent anticonvulsant and antiepileptic agent in several animal models, including kindling, audiogenic seizures in Fring’s mice, 6-Hz corneal stimulation,^6,166 as well as in vitro and decreases synaptic transmission via adenosine in vitro.¹⁶⁷ The acute effects of 2DG may be mediated through a number of different downstream mechanisms, but one intriguing possibility is a decrease in the endogenous phosphorylation of GABA_A receptors (which renders them dysfunctional) by the glycolytic enzyme glyceradeldehyde-3-phosphate dehydrogenase.^168,169 Perhaps the most compelling effect of 2DG in the kindling model is decreasing the expression of brain-derived neurotrophic factor (BDNF) and its principal receptor, TrkB, via induction of the transcription factor NRSF (neuron restrictive silencing factor), a master negative regulator of neuronal genes. This fascinating study reveals a biochemical interruption of glycolysis that can result in downstream physicochemical modulation of transcription, yielding a powerful effect in retarding epileptogenesis.

While glucose inhibition may exert pleiotropic effects in animal seizure models, similar anticonvulsant actions have been achieved by diversion of glucose to the pentose phosphate pathway (PPP). Fructose-1,6-diphosphate (FDP), a glycolytic intermediate, has been shown to exert acute anticonvulsant activity in several seizure models in adult rats including kainate, pilocarpine, pentylenetetrazole, and kindling.^170,171 Indeed, FDP was more effective as an anticonvulsant than 2DG, KD, or valproate in these studies. The precise mechanisms through which FDP produces anticonvulsant effects remain unclear, but it is conceivable that this substrate may exert an antioxidant action because the NADPH generated through the PPP reduces glutathione.¹⁷²

Another fascinating dietary approach toward epilepsy treatment is based on the observation that seizures cause a deficiency in tricarboxylic acid cycle (TCA) intermediates (especially α-ketoglutarate and oxaloacetate). It has been hypothesized that “refilling” these deficient compounds (a process called “anaplerosis”) might oppose seizure generation. In support of this idea, the anaplerotic substrate triheptanoin was recently studied in both acute and chronic seizure models.¹⁷³ Mice fed triheptanoin exhibited delayed development of corneal kindled seizures and triheptanoin feeding increased PTZ seizure threshold in chronically epileptic mice that had undergone status epilepticus 3 weeks before PTZ testing.¹⁷³ Therefore, like 2DG, anaplerotic compounds appear to alter both acute and chronic seizure susceptibility. Anaplerosis represents a novel approach that expands the potential metabolic modifications that could be anticonvulsant or antiepileptic. Taken together, results from studies of KDs, 2DG, FDP, and anaplerosis suggest that shifts in the activity of certain metabolic pathways might be exploited to develop novel treatments for epilepsy.

KETOGENIC DIET AND NEUROPROTECTION

While a detailed discussion of the expanding literature on the neuroprotective properties of the KD is beyond the scope of this chapter, a brief discussion is warranted as such actions are intimately related to epileptogenesis and seizure propensity. Further, the neuroprotective potential of the KD is increasingly being explored in a number of neurological disorders (see below). The reader is referred to recent reviews for more details on this subject.^4,174–176

Ketone bodies and PUFAs – metabolic substrates that are both elevated in epileptic patients treated with the KD – have been shown to exert neuroprotective activity in neurodegenerative conditions associated with impaired mitochondrial function.¹⁷⁵ Ketone bodies appear not only to raise ATP levels in seizure-prone areas such as hippocampus,¹⁷⁷ but also diminish reactive oxygen species (ROS) production through increases in NADH oxidation⁹² and inhibition of mitochondrial permeability transition.¹⁷⁸

Other than effects on voltage-gated ion channels, PUFAs - through induction of PPARα and its co-activator PGC-1 (peroxisome proliferator-activated receptor γ coactivator-1) - induce the expression of mitochondrial uncoupling proteins, which are homodimers spanning the inner mitochondrial membrane and enable a proton leak from the intermembrane space to the mitochondrial matrix. The net effect of this action is to reduce ATP synthesis, reduce calcium influx into the mitochondrial matrix, dissipate heat, and reduce ROS production.^179,180 The protective consequences of UCP activation have been detailed in a number of published reports.¹⁸⁰ One study demonstrated that dietary enhancement of UCP expression and function in immature rats protected against kainate-induced excitotoxicity, most likely by decreasing ROS generation.¹⁸¹ Further work demonstrated that mice maintained on a high-fat KD demonstrated an increase in the hippocampal expression and activity of all three brain-localized mitochondrial UCPs (UCP2, UCP4 and UCP5) and exhibited a significant reduction in ROS generation in mitochondria isolated from the same brain region.⁹⁰ Thus, it appears that a prominent neuroprotective mechanism of KD action involves a reduction in mitochondrial free radical production, which would decrease oxidative stress, and potentially neuronal injury.

FUTURE DIRECTIONS

To date, research efforts aimed at elucidating the mechanisms of KD action have not yielded simple answers. It is becoming increasingly apparent that the relevant mechanisms are likely diverse and operate in a coordinated and potentially synergistic fashion. The ongoing quest is challenged by the inherent difficulties in understanding neuronal network activity, let alone metabolism in the context of disease states, and importantly, in the intact patient or animal. Despite these issues, the research reviewed herein provides a clearer link between metabolism and neuronal excitability, and further validates the emerging field of neurometabolism, especially as it relates to epilepsy.

Based on the foregoing discussion, there are broader clinical implications posed by the KD. As the mechanisms underlying the neuroprotective activity of the KD are fundamental to many disease processes, it should be no surprise that diet can profoundly influence brain function, and in a growing number of instances exert protective and potentially disease-modifying effects.^4,175,182 As examples, the KD (or various formulations of its key metabolic substrates) have been found to ameliorate a range of clinical disorders and/or experimental models such as autism and Rett syndrome,^183,184 pain and inflammation,¹⁸⁵ traumatic brain injury,^186–188 neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease,^189,190 brain cancer,^191–193 prostate cancer,¹⁹⁴ diabetes^195,196 and obesity.¹⁹⁷ It should be noted that some of these disorders are co-morbid with each other, thus presenting the opportunity to help ameliorate multiple diseases with a single therapy.

Of the many potential uses of the KD, brain cancer is perhaps one of the most compelling targets given the rising interest in identifying metabolic targets for intervention.¹⁹⁸ The theoretical basis for using the KD to treat cancer is that tumorigenesis relies heavily on glucose, whereas normal cells retain metabolic flexibility and can use ketones for fuel.^192,198,199 A calorically-restricted KD or other glycolysis-limiting treatment forces higher ketone production, putting maximal stress on the tumor cells and minimal stress on the normal cells.^191,192,198 Paradoxically, some aspects of the current standard of care for brain cancer may support tumor growth.²⁰⁰

Neurodegenerative diseases are universally associated not only with mitochondrial dysfunction but also inflammation, and inflammation is a hallmark of virtually every chronic disease process throughout the body. In addition to reducing pain and inflammation,¹⁸⁵ the KD appears to enhance motor and cognitive functioning in a model of multiple sclerosis.²⁰¹ Further evidence is provided by recent reports of the KD mitigating MPTP-induced neurotoxicity and microglial activation,¹⁹⁰ and encephalopathy and seizures in forms of fever-induced epilepsy.²⁰² Ultimately, reducing inflammation could be one of the most important disease-modifying effects of a KD.

In addition to inflammation, disrupted sleep and circadian rhythms are common co-morbidities with many diseases. Recent evidence in humans and animal models shows that a KD can improve sleep in children with epilepsy²⁰³ and circadian rhythmicity in epileptic Kcna1-null mice.⁶⁸ It is well-known that circadian disruption is associated with epilepsy, psychiatric disorders, and the prevalent metabolic syndrome.^204–207 Normalization of circadian rhythms alone could yield enormous clinical benefits.²⁰⁸

CONCLUSIONS

The evidence for a KD as a successful epilepsy treatment is clear. Multiple retrospective, multi-center and randomized prospective studies document consistent and significant clinical benefits. The true efficacy of dietary treatments for epilepsy may be underestimated as the KD is rarely used as a first-line therapy. Certainly, by the time the KD is initiated to thwart medically-refractory epilepsy, in some instances the severity of the epileptic condition may be too difficult to overcome. But remarkably, the KD works in the majority of patients who failed to respond to numerous antiepileptic drugs. A detailed understanding of key KD mechanisms could offer a meaningful adjuvant or ultimately the development of a “diet in a pill”.³ But while clinical applications of metabolism-based therapy appear to be growing rapidly, there is a continuing need to develop modified diet formulations with improved efficacy and tolerability (as well as palatability), and to identify new pharmacological targets for drug discovery.

It is often stated that no single mechanism is likely to explain the clinical effects of antiepileptic drugs, and certainly the same could be said for the KD. The challenge of finding key mediators of KD action is made ever more difficult by the intrinsic complexity of metabolic activity within neurons and glia, which, to be relevant to the epileptic condition, must be interpreted at network levels. In this chapter, we have reviewed a number of seemingly disparate variables proposed to collectively exert anticonvulsant (and potentially neuroprotective) effects. The important interrelationships are summarized in Figure 4. The fact that a fundamental modification in diet can have such profound, therapeutic effects on neurological disease underscores the importance of elucidating mechanisms of KD action. In summary, mounting interest and insight into the mechanisms of KD action have laid a promising foundation for metabolic therapy as an emerging strategy for neurological disorders.

Figure 4

Hypothetical pathways leading to the anticonvulsant effects of the ketogenic diet (KD). Elevated free fatty acids (FFA) lead to chronic ketosis and increased concentrations of polyunsaturated fatty acids (PUFAs) in the brain. Chronic ketosis is predicted (more...)

ACKNOWLEDGMENTS

The authors thank Thomas V. Dunwiddie, Philip A. Schwartzkroin, John H. Schwartz, and Michael A. Rogawski for mentorship, and David N. Ruskin for assistance in preparing this manuscript. Supported by National Institutes of Health NS070261 and NS065957, and National Science Foundation IOS-0843585.

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