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Importance of magnesium depletion with hypofunction of the biological clock in the pathophysiology of headhaches with photophobia, sudden infant death and some clinical forms of multiple sclerosis


Magnesium Research. Volume 17, Number 4, 314-26, December 2004, Original article


Summary  

Author(s) : Jean Durlach, Nicole Pagès, Pierre Bac, Michel Bara, Andrée Guiet-Bara , Université Pierre et Marie Curie, Paris VI, 75252 Paris Cedex 05, France, Laboratoire de Toxicologie, Faculté de Pharmacie, Strasbourg, 67400 Illkirch-Grafenstaden, France, Laboratoire de Pharmacologie, Faculté de Pharmacie, Paris XI, 92290 Chatenay-Malabry, France, Laboratoire de Physiologie et Pathologie, UPMC, 75252 Paris Cedex 05, France.

Summary : Mg depletion is a type of Mg deficit due to a dysregulation of the Mg status. It cannot be corrected through nutritional supplementation only, but requires the most specific correction of the dysregulating mechanism. Among those, Biological Clock (BC) dysrhythmias are to be considered. The aim of this study is to analyze the clinical forms of Mg depletion with hypofunction of the Biological Clock (hBC). hBC may be due to either Primary disorders of BC [Suprachiasmatic Nuclei (SCN) and pineal gland (PG)] or Secondary with homeostatic response [reactive Photophobia (Pφ)] to light neurostimulating effects [Nervous Hyper Excitability (NHE)]. The symptomatology is mainly diurnal and observed during fair weather (Spring,Summer). The elective marker of hBC is represented by a decrease in melatonin and in its metabolites in various fluids. The clinical forms of NHE due to Mg depletion with hBC are central and peripheral. The central forms associate anxiety, headaches and dyssomnia. The peripheral manifestations are neuromuscular: photosensitive epilepsia mainly. Three chronopathological forms of Mg depletion with hBC have been highlighted: 1. Headaches with Pφ: mainly migraine; 2. Sudden Infant Death Syndrome (SIDS); 3. Multiple Sclerosis (MS).- Headaches with Pφ, migraine particularly. These cephalalgias are diurnal with Pφ and are aggravated during the fair seasons (particularly during midnight sun-summer). Migraine is their typical form with its dishabituation to visual stimuli and its occipital cortex hyperexcitability. Comorbidity with anxiety is frequent. In 2/3 of the cases, it appears first.- SIDS might be linked to an impaired maturation of both photoendocrine system and brown adipose tissue.- MS may be associated with primary disorders of BC Clinical forms of Mg depletion with hBC in MS present diurnal exacerbations and relapses during fair seasons. They have been underestimated because they disagree with the dogma of the « latitude gradient », presently questioned. Comorbidities with anxiety and migraine are frequent.hBC may be treated by using darkness therapy with a balanced Mg status. Absolute light deprivation should only be used only in acute indications and is time-limited. Partial substitutive therapy and chromatotherapy have not been validated yet and are still uncertain.

Keywords : magnesium, chronobiology, anxiety, headache, migraine, sudden infant death, multiple sclerosis

Pictures

ARTICLE

Auteur(s) :, Jean Durlach1,*, Nicole Pagès2, Pierre Bac3, Michel Bara4, Andrée Guiet-Bara4

1Université Pierre et Marie Curie, Paris VI, 75252 Paris Cedex 05, France
2Laboratoire de Toxicologie, Faculté de Pharmacie, Strasbourg, 67400 Illkirch-Grafenstaden, France
3Laboratoire de Pharmacologie, Faculté de Pharmacie, Paris XI, 92290 Chatenay-Malabry, France
4Laboratoire de Physiologie et Pathologie, UPMC, 75252 Paris Cedex 05, France

Introduction

The Biological Clock (BC) and the magnesium status are strongly correlated. The efficiency of the biological clock represented by suprachiasmatic nuclei and pineal gland is related to the quality of magnesium status [1].

A body of evidence has already stressed the difference between two types of magnesium deficit:

  • deficiency linked to an insufficient intake which may be corrected, over a long period of time, through a physiological nutritional oral magnesium supplementation,
  • depletion due to a dysregulation of the magnesium status which cannot be corrected through nutritional supplementation only, but requests the most specific correction of the dysregulating mechanism. There exist as many clinical forms of magnesium depletion as many possibilities of the dysregulation of the magnesium status. But in both clinical therapeutics and in animal experiment, the dysregulating mechanisms of magnesium depletion associate a reduced magnesium intake to various types of stress [2]. Among these, are biological clock dysrhythmias. This allows to distinguish the different manifestations of chronopathological forms of magnesium depletion among various pathologies including migraine, fatigue, fibromyalgia, dyssomnia, epilepsia and even sudden infant death syndrome [1, 3, 4].

The aim of the present study is to analyze the clinical forms of magnesium depletion with hypofunction of the Biological Clock (hBC). hBC may be due to either Primary disorders of BC [Suprachiasmatic Nuclei (SCN) and pineal gland (PG)] or Secondary to light neurostimulating effects,with their homeostasic response [reactive Photophobia (Pφ)].

Clinical forms of magnesium depletion with hypofunction of the biological clock

The biological clock hypofunction may be due to either primary disorders of BC or secondary homeostasic reactive response to light hypersensitivity linked to light neurostimulating effects. The organism responds to the pathogenic effect of this hypersensitivity by protective reactive photophobia, whose mechanism is still unclear [5].

The clinical characteristics of these secondary forms of chronobiological Nervous HyperExcitability (NHE) are of circadian as well as of seasonal type: the symptomatology is mainly diurnal and observed in spring and summer, when light hyperstimulation is obviously maximum during daylight or during the fair seasons. The main biological characteristic is represented by a decrease in melatonin (or in its metabolite) levels in various fluids which has been previously reported as the elective marker of the biological clock [1, 3].

The clinical forms of Nervous HyperExcitability (NHE) are both central and peripheral.

  • The central forms associate psychic, algic and hypnoid manifestations:
    • anxiety as manifested from generalized anxiety disorders (GAD) to panic attacks (PA) [6],
    • diurnal cephalalgia with photophobia aggravated during the fair seasons (and mainly during the polar summer [7]) whose type is migraine with its occipital cortex hyperexcitability [5, 8-10],
    • dyssomnia mainly represented by the delayed sleep phase syndrome (DSPS) observed for instance in jet lag, night work disorders, or insomnia of elderly patients [1, 3, 5, 11] with sometimes inappropriate behaviour [12]. Some chronopathological forms of sudden infant death syndrome (SIDS) may be also associated here [1, 4];
  • The central and peripheral manifestations are neuromuscular; mainly represented by photosensitive epilepsia, which may be either generalized or focal, authentified through EEG with intermittent light stimulation (ILS) with its corresponding form observed among TV viewers and video game players [3, 13-15]. Some migraine equivalents may be associated in this context. It is noteworthy that paradoxically epileptic activity may be induced by a light hyperstimulation or its suppression as well [3, 16].

The nervous form of chronopathological magnesium depletion may appear clinically as chronic fatigue syndrome (CFS) [17, 18] or as fibromyalgia [3, 19].

All the clinical magnesium depletion forms with biological clock hypofunction may coexist with the same chronobiological characteristics (mainly a decrease in melatonin or in its metabolite levels), the main comorbidity being represented by the association migraine-epilepsia [3] (( figure 1 )).

Chronopathological forms of magnesium depletion with hBC

Three chronopathological forms of magnesium depletion with hBC will be highlighted: headaches with photophobia (mainly migraine), some clinical forms of sudden infant death syndrome and of multiple sclerosis

Headache with photophobia, migraine particularly

The most typical form of biorhythm-type cephalalgia is migraine headache with photophobia [7, 8, 20-26]. These migraineurs have headaches during artic summers with continuing bright light (particularly during midnight-sun summer) and are in good condition during artic winters [7].

Nature of the magnesium deficit in migraine

Nervous hyperexcitability in migraineurs may be linked to magnesium deficit.

When chronic primary magnesium deficiency coexists with migraine, it only constitutes a decompensatory factor whose control with simple oral nutritional magnesium supplementation should help in migraine therapy as an adjuvant treatment: magnesium deficiency does not constitute the cause for migraine « per se » [27, 28].

Clinical studies on magnesium status in migraineurs have shown heterogeneous and inconstant decreases in extra or intra-cellular, total or ionized magnesium concentrations in serum, saliva, erythrocyte, mononuclear cells, thrombocyte, even in brain. Positive therapeutic response to oral physiological load is unreliable. These data agree with some dysregulation of the magnesium status in migraine that is to say magnesium depletion. The importance of the chronopathologic disorder in the aetiopathogenic mechanisms of the migraine, magnesium depletion should be highlighted [1, 3, 27-44].

Migraine and photic dishabituation

Habituation is a physiological phenomenon characterized by a decrease of the responses to repetitive stimuli: habituation is considered to be a protective mechanism against overstimulation.

Dishabituation, by contrast, is a process that liberates the nervous system from the habituation process. The dishabituation stimuli act as sensitization or potentiation processes which rely on a dysfunctionning of cortical information processing that might result from the high level of cortical arousal with increased energy demands and hypofunction of subcortico-cortical pathways. The cortical arousal level depends on the actions of various neurotransmitters from the brainstem projecting to the cortex. 5HT (serotonin) acts as a gain control between a noradrenergic, unspecific, facilitating system and a cholinergic, specific, inhibitory system.

Dishabituation may finally induce generalization: the alteration being able to involve other stimuli or to invade other substrates [45-49].

Migraine and magnesium depletion by photic sensitization

Migraine may be considered as the type of a chronopathological form of Mg depletion with hypofunction of the biological clock.

Subcortical and cortical genetic factors further the development of a magnesium depletion caused by a deficient magnesium dietary intake (magnesium deficiency) plus a photic stress [mainly circadian: (diurnal) and seasonal: (during « fair» seasons)] with reactive photophobia and more or less generalized [sensory, cognitive, painful (trigeminal particularly), alimentary] sensitization. It induces cortical and subcortical dysexcitability and spreading oligemia and depression in clinical forms with aura.

Dynamic study of dishabituation shows, during the interictal period of migraine, that response to various stressful stimuli overloads a metabolic strain on the brain of migraineurs. This increases the energy demands, triggers the activation of the trigemino-vascular sytem and leads to migraine attack.

During the ictal period, dishabituation and a higher level of cortical arousal can be normalized.

And later regained in the next cycle of the disease.

This new physiopathological data on migraine reveal that a shift in the brain metabolic homeostasis could be the main factor for migraine attacks.

The importance of photic dishabituation in headaches with reactive photophobia has been shown in studies of visual evoked potentials particularly not only for migraine (its typical form) but also in all headaches with light hypersensitivity. Between migraine and this type of headache, many authors have suggested a continuum of varying severity [1, 3, 39, 42-66] (( figure 2 )).

Sudden Infant Death Syndrome (SIDS)

SIDS may be due to gestational Mg deficit: Mg deficiency or various forms of Mg depletion [67].
  • SIDS may be caused by the fetal consequences of maternal Mg deficiency through an impaired control of Brown Adipose Tissue (BAT) thermoregulation, a mechanism leading to a modified temperature set point. SIDS may result from dysthermias: hypo- or hyperthermic forms. A possible prevention could rest on simple nutritional maternal Mg supplementation [4, 67];
  • Various stresses in pregnant women or in the infant may convert a simple Mg deficiency into Mg depletion: stress in baby care such as bedding in prone position, environmental factors such as parental smoking, but the role of chronopathological stress appears to be too often neglected although it constitutes a clinical form of primary hypofunction of the biological clock [with its anatomical and clinical stigma such as reduced production of melatonin (↓ MT) and of its urinary metabolite: 6 Sulfatoxy-Melatonin (↓ 6SMT)]. SIDS might be linked to an impaired maturation of both photoneuroendocrine system and brown adipose tissue (BAT) [4, 67].

Multiple Sclerosis (MS)

Some clinical forms of multiple sclerosis may be associated with primary disorders of magnesium status and of the biological clock (BC).

Magnesium depletion in Multiple Sclerosis

Several markers of the magnesium status have been studied in Multiple Sclerosis patients: decreased ionized magnesium concentration with normal total magnesium in plasma and serum, significantly decreased magnesium concentration in erythrocyte, decreased magnesium in brain especially in white matter without a decrease of myelin magnesium and with magnesium normal cerebrospinal fluid (but with decreased magnesium concentration in liver, spleen, heart and lung), low magnesium levels in rains and soils.

These various markers of Mg deficit may not be due to Mg deficiency, but testify to a clinical form of Mg depletion. We have highlighted the possible importance of several types of Mg depletion in the aetiopathogenesis of diverse neurodegenerative diseases, particularly of Mg depletion caused by the association between a nutritional factor: insufficient intake of magnesium (that is to say Mg deficiency) and neurostress (i.e. organic or inorganic neurotoxin, viral or parasitic neuroinfection, radiation, chronopathological stress ...). This study will mainly focus on the importance of the chronopathological stresses involved in multiple sclerosis [1, 3, 28, 29, 68-77].

Clinical forms of Multiple Sclerosis with biological clock dysfunction

Multiple Sclerosis (MS) remains a neurological disease of unknown aetiology but it has been recognized since the early nineteenth century that it is a disease with a unique distribution. Rare in equatorial regions, it becomes increasingly common in higher latitudes. « There is an increased risk of acquiring multiple sclerosis in adult life the greater as the distance that a person has lived away from the equator during childhood and adolescence » [78]. The importance of this latitude gradient has been stressed in several following epidemiological studies. Various climatic variables which significantly influence the risk of multiple sclerosis when analyzed alone (hours of sunshine particularly) are found when they are adjusted for latitude to be due to their correlation with this variable [79-82].

Poor photo-stimulation (in winter particularly) may be a factor of increased melatonin production, that is to say of a biological clock hyperfunction [83]. Constantinescu et al. have shown that luzindole, a melatonin receptor antagonist, suppresses experimental autoimmune encephalomyelitis (a classical model for multiple sclerosis) [84], but these data have not been confirmed by Maestroni [85]. Phototherapy (which suppresses melatonin production namely) seems rational in this clinical form of multiple sclerosis. Its protective effect may be due not only to melatonin suppression but also to depression of immune response, suppresssion of inflammatory leukotrienes and cytokines and to increased production of vitamine D (through ultra violet radiation particularly) [1, 70, 86-92].

Further research, with investigations of melatonin (MT) and of its urinary metabolite 6 sulfatoxy-melatonin (6SMT) production particularly, will be necessary to determine the frequency of this clinical form of Multiple Sclerosis with Biological Clock Hyperfunction (MS with HBC).

Conversely the importance of the clinical form of Multiple Sclerosis with Biological Clock hypofunction (MS with hBC) has been better documented. The main marker of the biological clock, the nocturnal plasma melatonin levels are decreased in multiple sclerosis patients. Although melatonin levels were unrelated to the patient age and gender, there was a positive correlation with age of onset of symptoms and an inverse correlation with the duration of illness. Physiological and chronobiological factors for decrease in melatonin production are similarly deleterious factors for multiple sclerosis: neonatal period, puberty, delivery; diurnal, seasonal and climatic photostimulation.

Multiple sclerosis may directly induce lesions of the Biological Clock. Hypothalamic lesions are frequent in multiple sclerosis. « Systematic pathological investigation of the hypothalamus in multiple sclerosis reveals an unexpected high incidence of active lesions that may impact on hypothalamic functioning » [103]. They may concern anterior hypothalamus where the mammalian circadian oscillator (the SupraChiasmatic Nuclei) is located. The prevalence of Pineal Calcification on Computerized Tomography (CT) scan was seen in 100% of studied multiple sclerosis patients. Hypofunction of Biological Clock (hBC) may be caused by Primary alterations of the Biological Clock and/or due to Secondary factors of hypofunction, seasonal and climatic factors particularly [1, 3, 67, 93-104].

The previously described NORTH-SOUTH gradient is inkeeping with a chronopathological form of multiple sclerosis with Hyperfunction of the Biological Clock (HBC), where the effects of sun light were beneficial. Low latitude decreases the risk for multiple sclerosis. But conversely many epidemiologic data have shown numerous exceptions to the theory of the latitude gradient.

They highlight the noxious effects of photostimulation through migration studies, cluster (or high frequency zone) studies, case controls studies. They agree with chronopathological forms of multiple sclerosis with hypofunction of the Biological Clock (hBC) with a decreased level of melatonin (↓ MT). This climatic factor of noxious photostimulation may be associated with synergic effects of diurnal and seasonal sun exposure: deleterious effects of sunbathing and of higher photostimulation during fair seasons: spring and summer. Similarly fair skin was associated with an increased risk for multiple sclerosis [1, 3, 76, 81, 82, 90, 105-117].

Three types of comorbidities should be stressed: anxiety, sleep disorders and migraine:

  • Anxiety disorders (panic attack and generalized anxiety disorder) are common in multiple sclerosis and frequently overlooked. This is often due to the difficulty differentiating anxiety from personality correlates, or reactive tendencies in patients with chronic neurologic disease. Anxiety in patients with multiple sclerosis is more often comorbid with depression than alone. Anxiety rating scales median score were respectively 18 in the multiple sclerosis patients (14 in chronic rhumatoid disease) and 6 in the healthy controls [3, 96, 118-124];
  • Sleep disturbances in multiple sclerosis are common but heterogeneous: from hypersomnia to various types of dyssomnias.A number of circadian rhythm sleep disorders may be observed: a delayed sleep phase syndrome is inkeeping with hypofunction of the Biological Clock (hBC). In subgroups of multiple sclerosis patients, sleep latencies may be reduced: the decrease of mean sleep onset latencies agrees with sleep disorders in magnesium deficit. The studies of sleep disturbances disagree for a generalized circadian disturbance in multiple sclerosis patient, but in subgroups, sleep studies show sleep disorders which are inkeeping with a clinical form of multiple sclerosis induced by magnesium depletion with hypofunction of the biological clock [28, 125-131];
  • Migraine may be associated with multiple sclerosis but its incidence has not been clearly established perhaps because the diagnostic criteria of migraine are difficult to identify among the diverse neurologic symptoms of multiple sclerosis. Watkins et al. found a 27% incidence of migraine in a cohort of 100 consecutive multiple sclerosis patients compared to a 12% incidence in a random selection of age-matched controls. These patients were reported also have twice the incidence of migraine in their family members. Besides cooccurence of multiple sclerosis and migraine, a high incidence of family history of migraine in multiple sclerosis patients is also observed. In another study of 104 consecutive patients the incidence of migraine was 8% [137]. Zorzon et al. assessed the risk of multiple sclerosis after information related to demographic data, socio-economic status, education, ethnicity, changes of domicile, migration, occupation, environmental, nutritional and hormonal factors, exposure to various infections agents, vaccination and family history of diseases. In multiple logistic regression analysis, they found four independent risk factors for multiple sclerosis. Migraine was one of these four risk factors and was frequently comorbid with multiple sclerosis. This comorbidity may rely on increased plasma levels of endothelin-1: a potent vasoconstrictor and a mediator in the inflammatory process [through matrix-protease 2 (MMP2) particularly]. These disorders are inkeeping with the well-known similar disturbances due to magnesium deficit, while the noxious effects of sun exposure agrees with a subgroup of multiple sclerosis with hypofunction of the biological clock [3, 20, 28, 75, 100, 108, 132-140].

These various aspects of Biological Clock hypofunction may be treated by darkness therapy [1, 3, 4, 67].

Darkness therapy

The psycholeptic (or sedative) properties of darkness therapy mirror the psychoanaleptic (or stimulant) properties of phototherapy.

Complexity of the mechanisms [1]

The mechanisms of the action of darkness appear as the reverse of those obtained with bright light where direct cellular effects (membraneous and redox) and neural mediated effects intervene.

Increased production of melatonin (↑ MT) constitutes the best marker of darkness, but it is only an accessory mechanism in the action of darkness.

The main central neural mechanisms of darkness therapy associate decreased serotonergy (↓ 5HT) - which could account for the antimigraine effect - and stimulation of inhibitory neuromodulators (↑ GABA, ↑ TA, ↑ kO) and of anti-inflammatory and antioxidative processes - which may induce neural-hypoexcitability (sedative and anticonvulsant effects).

Humoral transduction may reinforce these last effects by decreasing neuroactive gases (↓ CO, ↓ NO) through binding of CO with Hb and by increasing melatonin, bilirubin and biliverdin: three antioxidants which have the capacity to quench NO

Apart from the exception of decreased serotonergy, these effects of darkness are similar to those of magnesium [1].

Methods [1]

Darkness therapy per se

Light deprivation may be obtained by placing the patient in a closed room, in a totally dark environment, with an eye mask on.

This genuine darkness therapy may be used in acute indications, but should be of short duration. It is not compatible with any activity and is frequently associated with induction of bed rest, inactivity and sleep [1, 141].

Relative darkness therapy may be obtained by wearing dark goggles or dark sun glasses but the number of lux passing through is not negligible. This relative darkness therapy may be used as an accessory treatment in the restoration of a light dark schedule: a transition before a totally dark environment [1].

Darkness mimicking agents

Melatonin (MT) is the prototype of darkness mimicking agents. But it appears to be only an accessory factor among the mechanisms of photoperiod actions. Most of the other mechanisms of the effects of darkness have been overlooked, which may account for the controversy around the therapeutic efficiency of MT. Its posology varies from physiological doses (around 0,3 mg) to pharmacological doses (which testify to the weak toxicity of the hormone): usually 3 mg/per dose and per day and even up to 300 mg as a contraceptive. In case of chronopathology, with decreased MT production, MT constitutes a substitutive treatment of its deficiency [1].

Magnetic fields may be used to stimulate the biological clock in a variety of ways to treatment using very weak (picotesla), extremely low frequency (2 to 7 Hz) electromagnetic fields. Transcranial treatment with alternative currents pulsed electromagnetic fields of picotesla flux density may stimulate various brain areas (hypothalamus particularly) and pineal gland (which functions as a magneto receptor). Several studies on its use for treatment of anxiety, migraine and multiple sclerosis particularly [142-147] stressed «the beneficial effects of electromagnetic fields treatment on mood, level of fatigue and cognitive functions with improvements in short and long term memory, alertness, level of energy, concentration, attention, word finding, reading ability, visuospatial and visuoconstructive skills. But the neurological community, the multiple sclerosis organizations and the press remained uninterested in this revolution in multiple sclerosis management» [143]. However a double blind placebo controlled trial has shown that this therapy can alleviate symptoms of multiple sclerosis, although the clinical effects were small [147].

Chromatotherapy uses a short exposure (4 min) to a precise wavelength spectrum: orange or green for the treatment of hypofunction of biological clock. This method, even successfully used in practice, has not been validated yet [1, 3, 4].

Magnesium, L tryptophan and taurine may also act as darkness-mimicking agents.

To stimulate the biological clock, it seems well advised to facilitate the neural function of suprachiasmatic nuclei (↑ SCN) and the hormonal pineal production (↑ MT). The deleterious effects of light and those of magnesium deficiency are often found together and might be partly palliated by a nutritional magnesium supply (↑ Mg), providing the best possible link between photoperiod and magnesium status [1, 3, 4] (for example the preventive treatment of SIDS must be completed by the prophylactic therapy of its possible chronopathological factor: atoxic nutritional magnesium supplementation for pregnant women and total light deprivation at night for infants over the first year, this latter prescription in agreement with several pioneering studies [4, 67, 148-153]).

Pharmacological use of magnesium is uncertain and apt to induce toxicity. Choice and dose of the Mg salts, oral or parenteral route and indications for the mother or the infant, association with « Mg-fixing agents » remain imprecise [4, 154, 155].

  • Supplementation in L tryptophan (↑ LTP) may stimulate the tryptophan pathway but may induce toxicity: eosinophilia-myalgia syndrome particularly [1, 3, 4, 156-163];
  • Taurine (↑ TA) may act as a protective inhibitory neuromodulator which participates in the functional quality of the neural apparatus and in melatonin production and action. Taurine plays a role in the maintenance of homeostasis in the central nervous system, during central nervous hyperexcitability particularly. Taurine a volume-regulating aminoacid is released upon excitotoxicity induced cell swelling. Taurine has an established function as an osmolyte in the central nervous system [1-4, 28, 29, 164-171].

Conclusion

The different clinical forms of magnesium depletion with hypofunction of the biological clock, psychic, algic, hypnic, neuromuscular disorders due to either primary disturbances of the biological clock (genetic, ontogenic, infectious or neurodegenerative disorders) or secondary to light hypersensitivity (with reactive photophobia) show the importance of the etiopathogenic chronopathological mechanisms.

Further research will be necessary to determine the place of the various modes of « darkness therapy associated with a balanced magnesium status » in indications as various as prevention of sudden infant death, migraine and multiple sclerosis.

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