Estrogen and stroke: a review of the current literature.
Stroke is one of the leading causes of death and disability annually, and one of the larger populations for which neuroscience nurses care. Differences in gender have been identified as a risk factor for stroke repeatedly throughout the literature. The purpose of this evidence-based literature review is to provide information to healthcare professionals regarding stroke and its relationship with estrogen, the major female sex hormone. Background information on the three types of stroke is outlined, and information on estrogen compounds and hormone replacement therapy is detailed. A review of articles relating estrogen and/or hormone replacement therapy with stroke was performed. Fifty-seven articles met the criteria for inclusion in the review, 19 articles support the use of estrogen and/or an estrogen-related compound in the prevention or treatment of stroke, 6 articles claim estrogen and/or estrogen-related compounds are risk factors for stroke, and 11 articles remain inconclusive with regard to an estrogen and stroke relationship.
Stroke (both ischemic [87%] and hemorrhagic [10%]) is one of the leading causes of death in the U.S. population, affecting approximately 780,000 Americans each year (Rosamond et al., 2008). Of these, approximately 157,000 people die of the event annually, and as many as 30% become permanently disabled (Thorn et al., 2006). Research on the incidence and outcome of stroke has repeatedly identified sex differences, although the causative factor(s) behind the effect of sex on stroke has not been established. Data show that recently postmenopausal women have a higher incidence of subarachnoid hemorrhage (SAH) and that women in general tend to have poorer outcomes after any stroke type than do men (Harrod, Batjer, & Bendok, 2006). One theory behind the difference in both the incidence and outcome of stroke based on sex is that hormonal factors, particularly estrogen (Bushnell et al., 2006), may play a role in these neurological insults. Conversely, estrogens have also been identified as providing neuroprotective effects in ischemic brain injury and continue to be studied in a variety of settings (Yang, Liu, Wu, & Simpkins, 2003). The purpose of this article is to present a literature review regarding the hormonal influences of estrogen, estradiol, and hormone replacement therapy (HRT) relative to the incidence and outcome of stroke.
Types of Stroke
Ischemic strokes occur when a blood vessel or vessels that supply the brain are occluded by either a thrombus or an emboli (American Stroke Association, 2006), causing decreased or absence of blood flow to brain tissue and leading to inadequate oxygenation and nutrient delivery. Risk factors for ischemic stroke include hypertension, atherosclerosis, heart valve defects, diabetes, atrial fibrillation, excessive blood-clotting factors (i.e., fibrinogen), elevated homocysteine, elevated low-density lipoprotein cholesterol, and increased age (American Stroke Association, 2006). The stroke incidence rates of women are higher than those of men at older ages (Rosamond et al., 2008). The male-to-female incidence ratio is 0.76 in those 85 years of age or older (Rosamond et al., 2008).
Intracerebral hemorrhage (ICH), or intraparenchymal hemorrhage, occurs when there is bleeding into the brain, typically as a result of a hypertensive episode. ICH is the least treatable, most disabling, and deadliest type of stroke (Ribo & Grotta, 2006). It causes cell death by direct tissue destruction, neurotoxicity, inflammation, edema, impairments in blood flow, and apoptosis (Auriat, Plahta, McGie, Yan, & Colbourne, 2005). Both hematoma formation and cerebral edema increase the deleterious effects of ICH. Fortunately, many risk factors are modifiable and include hypertension, diabetes, tobacco use, and alcohol abuse. Nonmodifiable risk factors include advanced age, race, and sex, with African Americans and men more likely to experience ICH (American Stroke Association, 2006).
SAH, the least common type of stroke, occurs when blood spills into the subarachnoid space. The majority (75%-90%) of all SAH occur as a result of either a ruptured intracranial aneurysm or trauma (Lin et al., 2006). Less common causes of SAH are arteriovenous malformations and mycotic aneurysms; however, approximately 10% to 20% of SAH do not have an identifiable source (Tatter, Crowell, & Ogilvy, 1995). Factors that pose a risk of SAH are the use of anticoagulant therapy, hemophilia and thrombocytopenic purpura, arterial dissection, and cocaine use (Weibers, 2001). Women typically experience SAH more frequently than do men, usually just after menopause. Also, women who have recently given birth are 28 times more likely to have a hemorrhagic stroke than the average person (Weibers, 2001). Consequently, the role of estrogen in the pathogenesis of SAH has been questioned repeatedly in connection with etiology of this stroke type.
Estrogen Compounds and HRT
Estrogens are steroid compounds that function as the primary sex hormone in females; progesterone also plays a major role. The three naturally occurring estrogens are estrone, estriol, and estradiol. From menarche to menopause, the primary form of estrogen in women is 17 [beta]-estradiol, which acts as a growth hormone for female reproductive organs. Estradiol is produced in the granulosa cells of the ovaries during puberty, through the process of aromatization of testosterone from the theca cells. Aromatase, the enzyme that converts testosterone to estrogen, is also produced by glial cells and neurons in the brain and by the cells of arterial blood vessels. Estradiol has been found to have an antioxidant neuroprotective function. Estrone is an estrogenic hormone secreted by the ovary and is the least prevalent of the three hormones. Estrone is relevant to health and disease because of its conversion to estrone sulfate, a precursor that can be converted to estradiol as needed. Estriol is more prevalent during pregnancy as it is produced by the placenta. Figure 1 shows a partial list of hormone metabolites.
[FIGURE 1 OMITTED]
Estrogens readily diffuse across cell membranes into the cell. Within the cell, they interact with estrogen receptors (ERs) on the nuclear membrane. 17 [beta]-Estradiol binds equally well to both ER [alpha] and ER [beta]. Estrone binds preferentially to ER [alpha], whereas estriol binds to ER [beta]. The binding of estrone, estriol, or estradiol to intracellular receptors forms a complex that binds to the hormone response element (a sequence of DNA occurring before a gene). These compounds influence gene transcription and thereby protein production (see Figure 2). Estrogen also influences gene transcription and protein production through its interactions with other proteins such as activator protein 1, Sp-1, and PELP-1. Figure 3 shows the movement and binding sites of estrogen.
Estrogens are also used in oral contraceptives and HRT; however, these are synthetic equine estrogens (conjugated equine estrogens [CEE]) and may have differences from endogenous human estrogen. The U.S. Preventive Services Task Force recommends against combination estrogen-progestin therapy (CEE and medroxyprogesterone acetate) on the basis of an overall balance of harm versus benefit (Abramson, 2004). Questions are repeatedly raised regarding the benefits and risks of HRT to menopausal women (Ahramson, 2004).
Materials and Methods
Search Strategy and Selection Criteria
Articles published between 1993 and 2008 in English-language journals indexed by Ovid, PubMed, CINAHL, and the Cochrane Database of Systematic Reviews were searched for original research articles that reported the potential association between estrogen or HRT and stroke. Key words used for the search were "estrogen," "estradiol," "hormone replacement therapy (HRT)," "stroke," "intracerebral hemorrhage," "ischemia," "subarachnoid hemorrhage," and "neuroprotection." In addition, bibliographies of articles that were generated from this search were reviewed to identify other potential articles. To be included in the literature review, the articles must have presented data regarding estrogen, HRT, the various types of stroke pathology previously reviewed, neuroprotection or risks associated with estrogen, or any combination of aforementioned topics.
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Data Extraction and Synthesis
Each article was reviewed by the lead author. Because the information gathered is heterogeneous in nature, a literature review was written to provide the reader with a clear concept of the evidence available. In this literature review, we classified levels of evidence of human studies based the American Association of Neuroscience Nursing Clinical Practice Guidelines. This ranking is similar to the U.S. Preventative Services Task Force classification for evidence based practice as well (see Table 1).
Background information on stroke and estrogen is provided, and then details regarding current literature exploring the relationship between estrogen and stroke are outlined.
From a total of 562 articles generated by the search, 57 met the criteria for inclusion in this review. Of these articles, 19 support estrogens as having a beneficial impact on cerebral health, either as a neuroprotective agent or a factor related to the reduction of stroke risk, 11 articles describe the neuroprotective effect of estrogen and estrogen-related compounds as inconclusive, and 6 depict estrogen and estrogen-related compounds as significant risk factors in the development of different types of stroke. The remaining articles were used to gather additional information for the readers.
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Positive Effects of Estrogens
Of the articles reviewed, 19 support the use of estrogen and estrogen-related compounds for a variety of reasons. Based on various experimental approaches, estrogen has been shown to affect hemorrhage volume, tissue survival, cerebral blood flow, and the immune response, all of which may affect the response to stroke and improve outcomes. Falkeborn and associates (1993) found that women taking HRT (either potent estrogen or CEE) had a reduced risk of stroke (all types, 30%-40%) (Class 2).
Ischemic hemorrhage is often accompanied by apoptosis (programmed cell death). In an animal model of ischemic stroke, Rau, Dubal, Bottner, Gerhold, and Wise (2003) found that ovariectomized rats pretreated with estradiol before middle cerebral artery occlusion had smaller infarcts. Although they did not find differences in infarct size 4 or 8 hours after stroke, there were significant differences at 16 and 24 hours poststroke. They found less DNA damage (fragmentation), that cell death began later, and that fewer cells died in animals pretreated with estrogen compared with those given only vehicle. These findings suggest estrogen protects neurons from apoptosis by reducing enzymatic activity and DNA damage (Rau et al., 2003). The finding of antiapoptosis-mediated neuronal protection from cerebral ischemia has been repeated by many other researchers (Carswell, Macrae, Gallagher, Harrop, & Horsburgh, 2004; Choi, Lee, Hong, & Lee, 2004; Dubal et al., 2001; Hurn & Brass, 2003; McCullough, Alkayed, Traystman, Williams, & Hurn, 2001; Shi et al., 2001).
Although there is minimal clinical research on the relationship of estrogen and ICH, several studies in animal models have suggested that estrogen may decrease hemorrhage volume, improve cerebral blood flow, and/or decrease neuronal cell death after injury. Auriat and associates (2005) found that rats given estrogen before an induced ICH had multiple early effects that may contribute to improved long-term outcome. Male rats receiving 17 [beta]-estradiol pretreatment had smaller hemorrhages 12 hours after ICH and decreased lesion size 7 days after ICH, although this did not translate into improved functional outcome (limb use asymmetry, horizontal ladder test, elevated beam and staircase) 1 month after ICH (Auriat et al., 2005).
Some studies using animal models have suggested that estrogen and/or its metabolites may decrease cerebral vasospasm, ischemia, and mortality after SAH. Yan and colleagues (2006) studied this relationship using a rat model of SAH (all male) with administration of hypoxia-inducible factor [alpha]-1 inhibitors, 2-methoxyestradiol (an estrogen metabolite), and tricyclodecan-9-yl-xanthogenate (a positive control). They found that animals treated with 2-methoxyestradiol had only mild cerebral vasospasm, whereas rats who were not treated had more severe cerebral vasospasm (Yan et al., 2006). They also found the animals treated with 2-methoxyestradiol had lower mortality and better functional outcomes as measured by neurological score than those animals that were not treated with 2-methoxyestradiol (Yan et al., 2006). Yang and associates (2001) also explored the role of estrogen on the response to SAH by comparing blood load, ischemia, and mortality between nonovariectomized and ovariectomized female rats who were and were not given 17 [beta]-estradiol (Yan et al., 2006). They found that the rats treated with 17 [beta]-estradiol had less ischemia and lower mortality rates than ovariectomized female rats not receiving 17 [beta]-estradiol (Yang et al., 2001). They did not, however, find significant differences in blood load (size of SAH). Others have found administration of 17 [beta]-estradiol after experimental SAH decreases cerebral vasospasm (Lin et al., 2006; Shih, Lin, Lee, Lee, & Hsu, 2006). Although animal models of SAH do not directly correlate with human aneurysmal SAH, these findings suggest a possible protective role of estrogen.
After SAH, administration of 17 [beta]-estradiol promotes vasodilatation in part by decreasing endothelin-1 (ET-1) (Lin et al., 2006). ET-1 can be found in increased levels in cerebrospinal fluid of patients with cerebral vasospasm after aneurysmal SAH, suggesting that ET-1-mediated vasoconstriction potentiates cerebral vasospasm after SAH (Kessler et al., 2005). 17 [beta]-Estradiol inhibits ET-1 production and attenuates cerebral vasospasm after experimental SAH (Kessler et al., 2005). Further studies relating beneficial effects of estrogen and SAH include the Yamada et al. (2003) study reporting an estrogen deficiency associated with fatal SAH in humans (Class 2).
Additionally, in a recent review article by Zhao and Brinton (2006), coadministration of two of three neuroprotective estrogens (17 [beta]-estradiol, equilin, and [DELTA]89-dehydroestrone) exerted a greater neuroprotective efficacy than individual estrogens in neurodegenerative insults through rat and human studies (Liqin Zhao, 2005) (Class 3).
Animal work has supported the potential neuroprotective role of estrogens in response to various types of stroke. However, there is additional literature on studies of both animal models and humans that suggests the relationship may be more complex.
Inconclusive Evidence of Estrogen and HRT in Stroke
Eleven articles were inconclusive in finding a beneficial or deleterious effect provided by estrogen and HRT on stroke prevention or management. Simon and associates (2001) found HRT with CEE (a complex formulation containing multiple estrogens) and progestin had no effect on the risk for any subtype of stroke among postmenopausal women with coronary artery disease (Class 1). Pedersen, Lidegaard, Kreiner, and Ottesen (1997) found that estrogen and combined estrogen-progestin replacement therapies had no influence on the risk of hemorrhagic stroke (SAH or ICH) in women 45 to 64 years old (Class 1). Petitti, Sidney, Quesenberry, and Bernstein (1998) explored the relationship between ischemic stroke and menopausal HRT use in postmenopausal women and found no change in risk (Class 2). Okamato et al. (2001) suggest that the combined effect of several variables related to menstrual and reproductive history may exert a greater influence on risk of SAH compared with a single menstrual or reproductive variable; early menarche (younger than 13 years) and nulligravidity were both associated with increased risk of SAH (Class 2).
Negative Effects of Estrogens
Some of the articles reviewed describe estrogen and HRT as variables that increase the risk of ischemic stroke. Thorogood (1998) reviewed epidemiological studies from 1969 to 1998 and found that the risk of ischemic and thrombotic stroke increases with increasing doses of estrogen (Class 3).
According to the Women's Health Initiative (WHI) (a trial that evaluated combination hormone therapy in older postmenopausal women at multiple international sites), HRT may increase the risk of ischemic stroke in postmenopausal women (Bushnell et al., 2006) (Class 2). In the WHI study, 5,310 women in the treatment group were given daily doses of 0.625 mg CEE versus placebo group (5,429 women). The combination therapies included CEE, medroxyprogesterone, and 17 [beta]-estradiol. The WHI study showed a 40% increased risk of ischemic stroke with administration of combined HRT compared with women in the placebo group (Hendrix et al., 2006). The Canadian Task Force went so far as to stop the WHI Estrogen Alone trial because preliminary analyses demonstrated no benefit related to coronary heart disease and an increased risk of thromboembolism and ischemic stroke (80.3%) (Abramson, 2004; Hendrix et al., 2006) (Class 1). Hendrix et al. (2006) found that the CEE increased the risk of ischemic stroke in generally healthy postmenopausal women with no increased risk of hemorrhagic stroke (Hen&ix et al., 2006) (Class 2). Johnston, Colford, and Gress (1998) found in a meta-analysis of observational studies that oral contraceptive use produces a small increase in the risk of subarachnoid hemorrhage, with a relative risk of 1.42 (95% confidence interval: 1.12-1.80; p = .004), after eliminating confounding effects of other factors (Class 3).
It is important to note that in the work in animal models showing neuroprotective effects presented earlier in this review, endogenous estrogen was administered to the animals. In the human studies showing negative affects of estrogen on stroke risk, synthetic estrogens were administered. This suggests that the form of estrogen available to the brain may significantly the increase risk of stroke as well as infarct size and functional recovery after stroke.
There is evidence to suggest the neuroprotective role of estrogen in ischemic response is dependent on ERs (Dubal, Shughrue, Wilson, Merchenthaler, & Wise, 1999); in fact, ER [alpha], not ER [beta], is the critical mechanistic link that mediates the ability of physiological levels of estradiol to protect against brain injury (Dubal et al., 2001, 2006). Estradiol exerts a powerful protective effect both in vivo and in vitro, and these actions are mediated by ERs (Wise et al., 2001). Wise and associates (2001) found that 17 [alpha] does not effectively interact with the ERs and is therefore not neuroprotective in mice. Wise et al. (2001) go on further to explain that the addition of ICI 182,780 (an ER antagonist), blocks the protective actions of estradiol. However, Zhao and Brinton (2006) suggest that ER [beta] may be a novel and therapeutic target for developing new estrogen therapies in that it reproduces estrogen's beneficial effects in the brain, but provides a safer pharmacological profile. Dubal and associates (2001) used knockout mice (genetically altered mice that do not express ER [alpha] or ER [beta]) to explore the role of these receptors in response to ischemia and found estrogen-mediated neuroprotection was preserved in the ER [beta] knockout mice but not in the ER [alpha] knockout mice. This shows that the neuroprotective effects of estrogen are dependent on the ER [alpha] but not ER [beta]. Taken as a whole, these studies further support the role of ERs in neuroprotection and their potential therapeutic use in ischemic stroke.
The new estrogen analogues that do not bind to ER [alpha] or ER [beta] are now being studied. They exhibit enhanced neuroprotective activity in in vitro studies. These analogues have been shown to be potent protectors of brain tissue from cerebral ischemia and reperfusion injuries (Simpkins et al., 2004). They also provide the additional benefit of being nonfeminizing hormones (Simpkins et al., 2004). Administration of an estrogen analogue that does not bind to the ER [alpha] or ER [beta] results in estrogen available for use in the brain and may therefore avoid the negative influences exerted by current HRT
Nurses often find themselves caring for stroke patients of different ages and sex, and the purpose of this review is to inform neuroscience nurses of the current literature correlating estrogen and stroke.
Many animal model studies are being performed at present, with exciting new evidence on the horizon.
Also, the Pretorius group has proven that 17 [beta]-estradiol increases the basal release of active tissue plasminogen activator in young postmenopausal women, which leads to enhanced vascular fibrinolytic function (Pretorius, Guilder, Guzman, Luther, & Brown, 2008). Although there is no conclusive practice regarding the use of synthetic or endogenous estrogen to treat or prevent stroke, much research is being performed that may lead to guidelines in the future.
Although the current literature review suggests that estrogen can provide neuroprotective benefits, the form of estrogen available and its specific site of action may significantly alter functional outcomes. Interventions to halt clinical trials of HRT were imposed to prevent women from further neurological insult, but investigations must be continued to better understand the role of sex hormones in stroke. Future work focusing on the development of a synthetic estrogen that avoids the dangerous side effects, but maintains the neuroprotective qualities that estrogen provides, is vital to women's health and the stroke community. Additional research should focus on the various forms of estrogens, differences between endogenous and synthetic estrogens, ERs, and the complex interplay of these factors and the development and response to stroke. This will support the physiological mechanisms driving the relationship between HRT and stroke risk and provide a method for potential intervention to improve the side effect profile of HRT. The evidence available regarding the influence of estrogen on stroke incidence and recovery is vital to the neuroscience nurse. Up-to-date information will assist in educating patients about stroke risk and estrogen use.
Estrogen and Stroke: A Review of the Current Literature
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CE TEST QUESTION
GENERAL PURPOSE OF THE CE ACTIVITY: To provide the registered professional nurse with an overview of research on the relationship of estrogen to stroke.
LEARNING OBJECTIVES: After reading this article and taking this test, you will be able to:
1. Describe the different types of strokes and estrogens.
2. Discuss the latest research on the relationship between estrogen and stroke.
1. Stroke types include all of the following except
a. subdural hematoma.
b. ischemic stroke.
c. intracerebral hemorrhage (ICH).
d. subarachnoid hemorrhage (SAH).
2. The annual percentage of people in the United States who die from stroke is
3. Studies of sex differences and the incidence and outcome of stroke report that
a. estrogen causes better outcomes for women from any stroke type.
b. causative factors have not been established.
c. testosterone provides neuroprotective effect in ischemic stroke in men.
d. hormonal factors other than estrogen result in women having better outcomes after stroke.
4. At older ages, ischemic stroke incidence is
a. similar to incidence at younger ages.
b. equal for men and women.
c. higher for men.
d. higher for women.
5. The type of stroke typically caused by a hypertensive episode is
b. ischemic stroke.
d. subdural hematoma.
6. The least treatable, most disabling type of stroke is
a. ischemic stroke.
d. subdural hematoma.
7. The type of stroke caused mostly by a ruptured intracranial aneurysm is
b. ischemic stroke.
c. subdural hematoma.
8. Just after menopause, the type of stroke women suffer from more than men is
a. ischemic stroke.
b. subdural hematoma.
9. Secreted by the ovaries and the least prevalent of female hormones is
10. The female hormone produced by the placenta is
11. The estrogen(s) used in oral contraceptives is/are
c. conjugated equine estrogens.
12. Of the 57 articles included in this review, only
a. 11 described estrogen neuroprotective effects as conclusive.
b. 19 supported estrogens as a factor in reducing stroke risk.
c. 6 depict estrogen as beneficial for cerebral health.
d. 27 were used only for additional information for readers.
13. Falkeborn (1993) found that women taking hormone replacement therapy (HRT) had
a. an increased risk of SAH,
b. a decrease only in ischemic stroke incidence.
c. a higher risk of ischemic strokes.
d. a reduced risk of all types of stroke.
14. Rau et al. (2003) suggest that estrogen protects cerebral neurons by
a. reducing enzymatic activity,
b. increasing apoptosis in neurons.
c. increasing positive enzymatic neural protection.
d. increasing cellular DNA activity,
15. Auriat (2005) found that estrogen given to rats before induced ICH
a. decreased cerebral blood flow.
b. increased hemorrhage volume.
c. may have contributed to improved long term outcomes.
d. increased lesion size within 7 days.
16. Using male rats in studies of SAH, fan (2006) reported that estrogen
a. increased cerebral vasospasm but decreased ischemia.
b. decreased cerebral vasospasm but increased mortality.
c. had no beneficial effect.
d. decreased cerebral vasospasm and ischemia.
17. Endothelin-1 affects stroke outcomes by
a. promoting vasodilation after SAH.
b. potentiating cerebral vasospasm after SAH.
c. increasing the presence of 176 estradiol.
d. neutralizing the effect of 17 [beta]-estradiol.
18. Zhao (2005) reported that co-administration of two neuroprotective estrogens in neurodegenerative insults
a. exerted greater neuroprotective efficacy than individual estrogens.
b. was no more effective than one neuroprotective estrogen.
c. resulted in more vasospasm but less hemorrhage.
d. had no effect on male rat subjects.
19. Pederson (1997) reported that estrogen and combined estrogen-progestin HRT among women 45-64 years old
a. increased the risk of hemorrhagic stroke.
b. decreased vasospasms.
c. had no effect on the risk of hemorrhagic stroke.
d. required multiple administrations to produce beneficial effects.
20. The Women's Health Initiative reported that combination hormone therapy resulted in
a. a 50% decreased risk of ischemic stroke.
b. a 40% increased risk of ischemic stroke.
c. the same risk for ischemic stroke as those who took a placebo.
d. the same risk for ischemic stroke as those who took single estrogen therapy.
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Erin Carwile, RN BSN, is a student in the Nurse Anesthesia Program, University of Pittsburgh School of Nursing, Pittsburgh, PA.
Amy K. Wagner, MD, is faculty in the Department of Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Elizabeth Crago, RN MSN, is a research associate and student in the Department of Acute and Tertiary Care, Pittsburgh School of Nursing, Pittsburgh, PA.
Questions or comments about this article may be directed to Sheila A. Alexander, RN PhD, at firstname.lastname@example.org. She is an assistant professor in the Department of Acute and Tertiary Care, University of Pittsburgh School of Nursing, Pittsburgh, PA.
TABLE 1. American Association of Neuroscience Nursing Clinical Practice Guidelines Class I Randomized, controlled trial without significant limitations or beta-analysis Class II Randomized, controlled trial with important limitations (e.g., methodological flaws, inconsistent results), observations studies (e.g., cohort, case control) Class III Qualitative studies, case study, or series Class IV Evidence from reports or expert committees and/ or expert opinion of the guideline panel, standards of care, and clinical protocols that have been identified
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|Author:||Carwile, Erin; Wagner, Amy K.; Crago, Elizabeth; Alexander, Sheila A.|
|Publication:||Journal of Neuroscience Nursing|
|Date:||Feb 1, 2009|
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