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Keywords:

  • BDNF ;
  • bipolar disorder;
  • estrogen;
  • inflammation;
  • menopause;
  • oxidative stress;
  • postpartum;
  • pregnancy;
  • premenstrual;
  • progesterone

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Disclosures
  8. References

Objectives

Previous studies have suggested that women with bipolar disorder are at higher risk for mood episodes during periods of intense hormonal fluctuation (e.g., premenstrual, postpartum, perimenopause). There is converging literature showing that estrogen and progesterone can modulate neurotransmitter systems and intracellular signaling pathways known to be affected by mood stabilizing agents. Here, we critically review clinical aspects of reproductive cycle events in women with bipolar disorder and preclinical studies, with a focus on the functional interactions between sex hormones and biomarkers of neuroprotection and neurodegeneration that are thought to be involved in the neurobiology of bipolar disorder: brain-derived neurotrophic factor, oxidative stress, and inflammation.

Methods

A MedLine search using estrogen, progesterone, brain-derived neurotrophic factor, oxidative stress, and inflammation as key words was conducted.

Results

Data showed that estrogen and progesterone closely interact with brain-derived neurotrophic factor, oxidative stress, and inflammation pathways.

Conclusions

This relationship between sex hormones and the pathways of neuroprotection/neurodegeneration may be relevant to the psychopathological aspects of bipolar disorder in women.

Pregnancy and, in particular, the postpartum are periods of substantial relapse in women with bipolar disorder (BD) [1]. Two re-analyses of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) found that the presence of premenstrual exacerbation is an independent risk factor for early relapse in women with BD [2] and that women with BD have an elevated risk of developing depressive episodes during the transition to menopause [3]. These studies suggest that some women with BD are more vulnerable to developing mood instability under periods of hormone fluctuation. Estrogen and progesterone are involved in several aspects of brain function, such as brain development, synaptic plasticity, and modulation of neurotransmitter systems [e.g., serotonin, norepinephrine, gamma aminobutyric acid (GABA), glutamate] [4]. Estrogen and progesterone receptors are found in brain areas involved with the stress response and mood regulation, including the hypothalamus, hippocampus, amygdala, and prefrontal cortex [5, 6]. Although previous studies have explored the link between sex hormones and other female-related mood disorders such as premenstrual dysphoric disorder (PMDD), (unipolar) postpartum depression, and perimenopausal depression [7-9], very little is known about the role of sex hormones in the pathophysiology of BD.

Clinical and epidemiological studies have revealed elevated rates of mood episodes/dysregulation in women with BD at specific periods of the female reproductive life cycle (premenstrual period, postpartum, and menopausal transition). For instance, studies that investigated the association between PMDD and BD suggest that the presence of PMDD is higher in individuals with BD and vice versa. In a large community-based study of the prevalence of PMDD (n = 902), Wittchen et al. [10] found an eight-fold increased incidence of comorbid BD in women with a DSM-IV diagnosis of PMDD (PMDD+) as compared to those without PMDD (PMDD−). Fornaro and Perugi [11] found that 27.2% of women with BD (n = 92) met the criteria for PMDD and that the presence of bipolar II disorder (BD-II), obsessive-compulsive disorder (OCD), cyclothymia, body dysmorphic disorder, and history of postpartum depression were independent predictors of PMDD. This is in line with a Korean study (n = 61 women with BD, 122 controls) that reported higher rates of PMDD among BD-II (22.6%) as compared to bipolar I disorder (BD-I) (6.7%) and controls (1.6%) [12]. In a one-year follow-up study (n = 293), Dias et al. [2] found that women with BD who reported premenstrual exacerbation of mood symptoms (depression or mood swings) had more depressive episodes and relapsed earlier than women with BD with no premenstrual exacerbation. Around two-thirds of the women (65.2%) in the latter study reported premenstrual exacerbation of symptoms at baseline. Although these studies suggest that women with BD have high rates of premenstrual mood symptoms, they contrast with a number of smaller and underpowered studies that failed to find an association between BD and premenstrual exacerbation when mood symptoms were prospectively monitored [13-16].

Some studies suggest that the occurrence of mood episodes during pregnancy may be high in women with BD. Data collected from 2,252 pregnancies in 1,162 women diagnosed with BD-I, BD-II, or major depressive disorder (MDD) referred to tertiary treatment centers showed that 22.7% of women with BD and 4.62% of unipolar women experienced a mood episode during pregnancy [1]. In this study, the diagnosis of BD and previous postpartum episodes were independent predictors of a mood episode during pregnancy. In a longitudinal study, women with BD who opted to discontinue the medications when they found out they were pregnant had a 2.3-fold increased incidence of recurrence during pregnancy [17]. In this study, the episodes were more likely to occur in the first trimester and were more likely to be depressive or mixed [17]. Other studies found that the presence of depressive symptoms during pregnancy predicts a higher risk for a postpartum episode [18, 19]. However, a recent systematic review on this topic concluded that the findings of an increased risk for mood episodes during pregnancy may have been driven by samples enriched with more severe cases [20].

The postpartum is a well-recognized period of substantial risk for relapse in women with BD. A recent large study showed that 52% of women with BD and 30% of unipolar women reported at least one postpartum episode [1]. The postpartum period is also associated with higher risk for psychosis (100 times higher than the prevalence found in the general population) and appears to run in families [21]. In fact, diagnosis of BD is the best predictor for psychiatric readmission within the first three weeks postpartum [22]. On the other side of the severity spectrum, the prevalence of postpartum hypomania in non-clinical populations ranges between 9.6% and 20.4% [23]. Using a standardized clinical interview, Sharma et al. [24] reported that 54% of patients with postpartum depression had a lifetime diagnosis of bipolar spectrum [bipolar disorder not otherwise specified (NOS) (29%), BD-II (23%), and BD-I (2%)]. However, only 10% of these cases had been correctly diagnosed.

Overall, studies that investigated perimenopausal and postmenopausal women with BD have reported that about 20–50% of women with BD experience intense mood symptoms during the menopausal transition [18, 25]. A longitudinal study that followed women with BD for an average of 18 months found that the frequency of depressive episodes was increased during the perimenopausal years as compared to their premenopausal years [3]. No differences were seen in terms of manic or hypomanic states, which suggests that the transition to menopause is associated with a higher risk for depression but not mania in women with BD. This study is consistent with two retrospective reports showing that BD is associated with reoccurrence of mood episodes at distinct reproductive cycle events [26, 27].

As reviewed above, clinical and epidemiological studies support the assumption that fluctuation of sex hormones can trigger mood episodes in women with BD. However, the molecular events that may underlie this association are largely unknown. Next, we critically review the interaction between ovarian hormones and intracellular signaling systems involved in the pathophysiology of BD: brain-derived neurotrophic factor (BDNF), oxidative stress, and inflammation [28, 29].

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Disclosures
  8. References

We performed a MedLine search using the key words estrogen, progesterone, brain-derived neurotrophic factor, oxidative stress, and inflammation. This initial search identified 1,358 abstracts. Articles were eligible for this review if they were published in English or Portuguese. Clinical and preclinical studies that did not investigate the central nervous system or peripheral blood (humans) were excluded. Priority was given to original studies but relevant review and positional papers were included. The final review included 101 articles.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Disclosures
  8. References

Functional interactions between sex hormones and biomarkers of neuroprotection and neurodegeneration

Sex hormones and BDNF

BDNF is a member of the neurotrophin family and is known to regulate neuronal maturation, differentiation, survival, neurotransmission, and synaptic plasticity. These effects in the central nervous system (CNS) involve the activation of its membrane receptors tropomyosin receptor kinase B (TrkB) and p75, which can activate a range of intracellular signaling cascades such as phosphoinositide 3-kinase-Akt (PI3K-Akt), mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), phospholipase C gamma (PLCγ), and Ca2+/calmodulin-dependent kinase (CAMK). Several lines of evidence suggest that BD is associated with decreased BDNF function. For instance, peripheral BDNF levels are decreased during manic and depressive episodes and are negatively correlated with the severity of manic and depressive symptoms [30, 31]. Moreover, peripheral BDNF is restored after successful pharmacological treatment in manic states [32, 33] and is lower in BD subjects with history of multiple episodes as compared to first-episode subjects [34]. A large meta-analysis (n = 1,113 subjects) concluded that BDNF may be a useful biomarker of mood state and progression of disease in BD [35]. CNS abnormalities in BDNF and its receptors in BD subjects have been described in the hippocampus [36, 37] and cerebellum [38], but not in the locus ceruleus [39]. Notably, a number of mood stabilizers and antidepressant agents have the ability to modulate BDNF expression and protein in the rat brain [40-44]. Together, these studies provide evidence supporting the role of BDNF in BD.

There has been converging literature highlighting functional interactions between estrogen and BDNF [45, 46]. In a seminal study, Sohrabji et al. [47] identified an estrogen response element binding site at the 5′ end of the exon IX of the BDNF gene. In this study, BDNF mRNA was upregulated in the cerebral cortex and olfactory bulb of ovariectomized (OVX) rats treated with estradiol benzoate, which indicates that estrogen can upregulate BDNF in forebrain neurons. Consistent with this latter finding, BDNF mRNA fluctuates across the estrous cycle in rodents [48, 49]. Although there is no current technique that permits BDNF or its receptors to be measured in the human brain in vivo, plasma BDNF levels were found to be higher during the luteal compared to follicular phase in fertile women [50, 51], but the opposite was seen in women with premenstrual syndrome (PMS) [51]. Fluctuations in peripheral BDNF levels across the menstrual cycle suggest a potential role for gonadal sex hormones in regulating neurotrophin expression and function, which would have implications for female-related mood disorders (e.g., PMS, postpartum, etc.). Studies looking at BDNF levels across the menstrual cycle in women with BD are awaited.

A number of neuroprotective effects of estrogen have been associated with estrogen's ability to regulate BDNF. For instance, estradiol (E2) rescued stress-induced downregulation of BDNF mRNA in the hippocampus of OVX rats [52]. Such an increase in BDNF expression was associated with attenuation of neuronal loss in the CA3 region and improvement in a recognition task [52], suggesting that an E2-induced increase in BDNF expression was associated with increased neuronal survival and better cognitive performance. Several independent studies have reported that estrogen upregulates BDNF signaling via fast, non-genomic effects [53-56]. For instance, Yang et al. [54] found that E2 exerts robust neuroprotective effects against global cerebral ischemia in the hippocampal CA1 region via a membrane-initiated cascade involving ERK-Akt-cAMP response element-binding (CREB)-BDNF signaling. Using hippocampal slice cultures, Sato et al. [55] found that E2-induced synaptogenesis between mossy fibers and the CA3 region by increasing BDNF release from dentate gyrus granule cells via rapid membrane–protein kinase A (PKA) signaling. The neuroprotective effects of estrogen through BDNF signaling do not seem to be restricted to hippocampal regions and have also been observed in midbrain [56] and striatal [53] dopaminergic neurons. In double-mutant mice deficient in serotonin transporter and BDNF, Ren-Patterson et al. [57] showed that female mice display a smaller reduction in TrkB expression and less serotonin and dopamine disturbance than their male counterparts. In this study, E2 also improved serotonin function in the hypothalamus when administered to male mice, which further reinforced the relationship between estrogen and BDNF in improving neurotransmission and behavior.

Investigations of the effects of progesterone on BDNF signaling are relatively scarce and controversial. Studies in vitro and in vivo indicate that progesterone inhibits or counteracts the positive effects of estrogen on BDNF in the hippocampus [58-60]. However, others have found either no evidence of a relationship between progesterone and BDNF in glioma or cerebellar granular cells [61] or an increase in BDNF expression in rat glioma [62] and cerebral cortical cultures [63]. In summary, there is evidence showing that estrogen and, to a lesser extent, progesterone have the ability to regulate BDNF signaling, thereby regulating neurotransmitter systems, neuronal survival, and synaptic plasticity.

Sex hormones and oxidative stress

Oxidative damage to lipids and proteins due to excessive generation of reactive oxygen species (ROS) and/or a decrease in enzymatic and non-enzymatic defenses (oxidative stress) are key processes in neurodegenerative disorders and cognitive decline associated with aging [64]. Several studies have demonstrated with remarkable consistency that individuals with BD have elevated circulating oxidative stress markers [65-67]. Recent postmortem studies have complemented studies in peripheral blood showing lipid and protein (including DNA and RNA) oxidative damage in various areas of the prefrontal cortex and hippocampus [68-71]. Preclinical data showed that lithium and valproate exert antioxidant effects in vitro [72, 73] and in vivo [74, 75], which suggests that the therapeutic effects of these mood stabilizers may involve, at least in part, a decrease in oxidative damage.

Several lines of evidence have demonstrated that estrogen and, to a lesser extent, progesterone can protect against a number of excitotoxic and oxidative insults [76, 77]. Notably, many of the neuroprotective effects of estrogen against oxidative stress have been associated with stabilization of mitochondrial function [78, 79]. An elegant study showed that E2 stabilized mitochondrial membrane potential and diminished lipid peroxidation and apoptotic rate in cybrids generated from patients with Leber's hereditary optic neuropathy, one the most frequent mitochondrial diseases caused by mutations in mitochondrial DNA [80]. In brain endothelial cells, E2 treatment increases mitochondrial energy efficiency and decreases the production of ROS, probably via activation of estrogen receptor alpha (ERα) [79, 81]. It has also been proposed that part of estrogen's antioxidant effect may be via repression of glutamate receptor-mediated calcium influx [82]. In this model, E2 reduced the hydrogen peroxide-induced activation of ERK signaling, thereby downregulating the ionotropic glutamate receptor subunits NR2A and GluR2/3, which ultimately reduced calcium influx. In female rat striatal neurons, membrane ERα activated the mGluR5–MAPK–pCREB cascade, whereas both ERα and estrogen receptor beta (ERβ) activated mGluR3 to attenuate L-type calcium channel-dependent CREB activation [83]. Finally, estrogen's neuroprotective effects against glutamate-induced cell death can be mediated in part by a recently discovered G protein-coupled ER, G protein-coupled receptor 30 (GPR30) [84]. Collectively, the above-mentioned studies revealed several mechanisms by which estrogen exerts neuroprotective effects against oxidative insults.

Many, but not all [85, 86], studies have found that progesterone can also induce antioxidant effects in the brain. A series of studies investigated the effects of E2, progesterone, and medroxyprogesterone acetate (MPA) on mitochondrial function in OVX rats [77, 85]. When administered alone, E2 and progesterone increased mitochondrial respiration and decreased the production of ROS, whereas MPA induced an overall decline in mitochondrial function. In addition, the beneficial effects of E2 and progesterone on mitochondrial function were not observed when E2 was administered in combination with progesterone or MPA [77, 85]. These studies have potential treatment implications in regard to hormone replacement therapy (HRT), considering that some beneficial effects from E2 and progesterone seem to disappear if they are administered concomitantly. Consistent with this, some studies reported that progesterone can decrease lipid peroxidation in vitro [87] and in vivo [88]. Also, progesterone has the ability to increase the activity of antioxidant enzymes [89, 90], although not as strongly as E2 [89]. Co-administration of progesterone prevented haloperidol-induced orofacial jerks and striatal lipid peroxidation in a rodent model of tardive dyskinesia [91]. Collectively, these studies provide compelling evidence suggesting that estrogen and progesterone can protect against a number of oxidative stress insults. Considering that abnormalities in oxidative stress markers are present in the CNS and periphery of individuals with BD, future studies should test whether women with BD exposed to contraceptive agents or HRT may exhibit a distinct oxidative profile as compared to those unexposed to hormonal treatments. In addition, studies looking at gender differences in oxidative profile and changes in oxidative stress markers during periods of marked hormonal fluctuation (e.g., postpartum, menopausal transition) may provide useful insights on the potential characteristics of oxidative profile in women across the reproductive cycle.

Sex hormones and inflammation

Investigation of inflammatory markers across mood states in BD revealed increased serum interleukin (IL) 2, IL-4, and IL-6 during mania and increased IL-6 during bipolar depression [92], but no significant differences in circulating cytokines between euthymic subjects and controls [92-94]. Although these studies suggest that peripheral cytokine levels rise during acute episodes in BD and normalize during remission of symptoms, one study found that certain chemokines – namely, C-X-C motif chemokine 10 (CXCL10) and chemokine (C-C motif) ligand 24 (CCL24) – are altered in euthymic BD subjects [95]. Moreover, serum tumor necrosis factor α and IL-6 are elevated early in the course of BD and remain elevated in multiple-episode BD subjects [34]. A recent twin-study suggested that alterations in inflammatory markers observed in monozygotic and dizygotic twins with BD seem to be driven by shared environment and not by genetic influence [96]. Postmortem studies found elevated cell adhesion molecule immunoreactivity in the anterior cingulate cortex [97], increased mRNA levels of IL-1β, IL-1R, and inducible nitric oxide synthase [98], and increased calprotectin [99] in the dorsolateral prefrontal cortex of individuals with BD. These studies indicate that the pro-inflammatory profile observed in peripheral blood may reflect inflammatory processes that occur in the CNS. The fact that the pro-inflammatory status in BD is highly influenced by the environment and sometimes resolves with remission of symptoms opens a venue for treatment strategies focused on modulators of inflammatory pathways. However, more studies are necessary in order to determine the extent by which improvements in mood symptoms precede or follow changes in inflammatory markers in BD.

Most of the studies that used in vivo lipopolysaccharide (LPS) models of systemic inflammation reported that E2 decreases pro-inflammatory cytokines and chemokines in the CNS [100-106]. However, some studies failed to find anti-inflammatory effects with E2 treatment [107, 108]. Using ERα and ERβ knockout mice, Brown et al. [100] showed that estrogen's cytokine- and chemokine-suppressive responses occur via both estrogen receptors through ligand-dependent and -independent mechanisms. Although estrogen exerts anti-inflammatory effects in astrocytes and microglia [102, 109], some studies have found that the anti-inflammatory response is more robust with selective activation of ERβ [102, 110]. An elegant study demonstrated that ERβ-specific ligands activate a specific intracellular signaling pathway (CtBP-AP-1) that ultimately represses genes that amplify inflammatory responses [110]. This is consistent with a recent study showing that E2 and specific ERα- and ERβ-specific ligands modulate the expression of neuroinflammatory genes in the frontal cortex of OVX rats [111]. These findings support the use/development of selective estrogen receptor modulators (SERMs) in neuropsychiatric diseases (such as BD) associated with increased inflammatory status. In this context, two small randomized controlled trials have revealed robust anti-manic effects with the ER- and protein kinase C (PKC) antagonist, tamoxifen [112, 113]. A four-week pilot study of 13 young women with BD also found that tamoxifen and MPA adjunctive to mood stabilizers alleviated manic symptoms more than placebo [114]. Together, these studies provide converging evidence showing that estrogen and estrogen modulators attenuate inflammatory responses in the CNS. Although some preliminary clinical trials encourage the use of SERMs in the treatment of BD, it remains to be determined whether or not such positive anti-manic effects are associated with a decrease in inflammatory or oxidative stress markers. Also, future studies should explore the potential anti-inflammatory effects of other hormones/neurosteroids (e.g., progesterone, allopregnanolone) in the CNS.

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Disclosures
  8. References

A significant proportion of women with BD face emotional challenges during periods of normal hormonal fluctuation [115]. Although it has long been recognized that the postpartum is a period of higher risk of relapse in BD, recent data suggest that the premenstrual phase and menopausal transition are also associated with an elevated risk of a mood episode [2, 3, 16]. Although these findings suggest that the physiological fluctuation of sex hormones may render some women more vulnerable to mood instability, research on the mechanisms behind this association is scarce. The investigation of biological models involving the role of estrogen, progesterone, and other sex steroids has the potential to generate new treatment strategies that could change the course of bipolar disorder in women.

As reviewed above, there is a growing body of literature showing that sex hormones have the ability to regulate intracellular signaling systems that are thought to be abnormal in BD. Thus, it is conceivable to believe that this functional interaction between sex hormones and molecules involved with synaptic plasticity and neurotransmitter systems may be associated with some of the clinical characteristics of women with BD (e.g., higher rates of BD-II, rapid cycling, mixed states, and threshold/subthreshold depressive mood). Another aspect that must be considered here is the fact that mood stabilizers can influence the levels of circulating hormones [116], or cause menstrual irregularity [117]. Given that the effects of estrogen at the molecular [46, 118] and behavioral [4, 58] level can vary depending on the availability of its endogenous ligands (i.e., hormonal milieu), this may in part explain why some women with BD complain of feeling ‘emotionally worse’ when taking certain medications. Although outside the scope of the present review, it is worth mentioning that sex hormones can also influence other important aspects of BD. For instance, estrogen and progesterone can modulate sleep and circadian rhythms [119, 120], anxiety/fear extinction [121], as well as processes of learning and memory [6]. Another possible role of progesterone in BD and its impact on mood stability were observed by Johansson et al. [122, 123] in two studies that linked progesterone levels with steroidogenic pathway activity. More specifically, they found that low progesterone levels during euthymia and polymorphisms in the AKR1C4 gene were associated with a history of manic/hypomanic irritability in males but not females [123]. They also observed that polymorphisms in the AKR1C4 gene were associated with less likelihood of paranoid ideation during manic episodes in both genders, and that lower serum levels of progesterone and dehydroepiandrosterone sulfate (DHEA-S) were associated with more paranoid ideation during mania/hypomania in men but not in women [122]. Progesterone and its metabolites can regulate the release of various neurotransmitters through a variety of mechanisms, such as rapid effects on ion channels, as well as through sigma-1, α-1 adrenergic, nicotine, D1, NMDA, and GABA receptors. In addition, DHEA levels are higher in the brain than in peripheral tissues, but the intrinsic mechanisms that regulate DHEA metabolism are not yet fully understood [124]. Plasma DHEA levels in BD patients were found to be higher when compared with controls and lower when compared with subjects with schizophrenia [125]. At least some of the neuroprotective effects of DHEA and its active metabolites occur via modulation of GABA and NMDA receptors and via anti-glucocorticoid activity [126-128]. Studies looking at DHEA's anti-inflammatory profile have found protective effects through the modulation of the microglia response after brain damage [129], as well as protection against brain oxidative injury in restrained stressed rats [130]. Lastly, there is also preclinical evidence of a possible interaction between DHEA, BDNF, and serotonergic activity in the brain, whereby BDNF would mediate DHEA's neuroprotective effects [131]. Although outside the scope of the present review, it is worth mentioning that other hormones, such as thyrotropin-releasing hormone and prolactin, may be involved in the relationship between BD and female reproductive life events [132, 133]. Furthermore, another fruitful area for future research in women with BD is the role of other neurosteroids (e.g., allopregnanolone) in mood and behavior [134, 135].

In conclusion, clinical data suggest that sex hormones influence some of the psychopathological aspects of BD in women but empirical evidence is still limited. The close relationship between sex hormones and molecular markers of neuroprotection and neurodegeneration (such as BDNF, oxidative stress, and inflammation) can set the stage for future research in this area. Not only could this potentially change the way we understand bipolar illness in women, but, more importantly, it could help in the development of new treatment strategies for this population at risk.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Disclosures
  8. References

The authors are thankful to Ms. Laura Garrick for her editorial support.

Disclosures

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Disclosures
  8. References

BNF has received grant/research support from the Alternative Funding Plan Innovations Award, Canadian Institutes of Health Research, Hamilton Health Sciences Foundation, Ontario Mental Health Foundation, Society for Women's Health Research, Eli Lilly & Co., and Pfizer; and has received consultant and/or speaker fees from AstraZeneca, Lundbeck, Pfizer, Servier, and Sunovion. RSD has no potential conflicts of interest to report.

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  3. Methods
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  5. Discussion
  6. Acknowledgements
  7. Disclosures
  8. References
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