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Regular Article |
Received December 1, 2001; revised April 10, September 14, 2002; accepted September 16, 2002. From the University of California, San Diego and VA Healthcare System, La Jolla, CA. Address correspondence to Igor Grant, M.D., Department of Psychiatry (0680), University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0680.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: Alzheimer's Disease • Stress • Caregivers
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Impact of Caregiving on Physical Health
A growing body of evidence suggests that caregiving has important ramifications for physical health.3,4 Not only have caregivers reported having poorer perceived health1 and a greater number of physical symptoms,5–11 but it has also been demonstrated that caregivers mount poorer immune responses to viral challenges,12 evidence slower rates of wound healing,13 and have significantly higher levels of plasma insulin14 than do age-matched control subjects. Longitudinal studies also demonstrate that caregivers are at a greater risk than non-caregiving age-matched controls for developing mild hypertension15 and have an increased tendency to develop a serious illness16 as well as increased risk for all-cause mortality.17
Altered hypothalamic-pituitary-adrenocortical (HPA) and sympatho-adrenal-medullary (SAM) activation are plausible explanations for the relationship between caregivers' stress and negative changes in caregiver health. In fact, several reviews document the relationship between stress, depression, and catecholamines (e.g., epinephrine, norepinephrine).18–20 Furthermore, the literature suggests that some caregiver subgroups, particularly those who experience high caregiving demand with little opportunity for respite, have increased peripheral markers of sympathetic nervous system and HPA activation. For example, caregivers who were classified as vulnerable to stress (based on a mismatch between amount of patient care required and the amount of respite available) have been found to have higher levels of plasma ACTH and catecholamines21 and fewer circulating CD8+62L–"memory" T-lymphocytes.22 Similarly, caregivers who simultaneously experienced additional life stressors had significantly higher plasma epinephrine levels than did either low-stress caregivers or non-caregiving age-matched controls,23 a condition we found to be associated with reduction in lymphocyte ß2-receptor sensitivity.
Interventions Reduce Caregiving Stress
Several critical reviews of caregiving-intervention literature24–30 note that these interventions differ in terms of modality (e.g., individual vs. group), patient population (e.g., spouse and/or adult child caregiver vs. patient with AD), theoretical underpinnings (e.g., Lazarus and Folkman model of stress-coping,31 the support theory of Barrera,32 the cognitive model of depression33) and service provided (e.g., respite, support, problem-solving, increasing pleasurable activities, cognitive restructuring, and multi-component).
Respite is one of the most common support services utilized by caregivers and has been identified by caregivers as the most important service to facilitate home care of frail elderly patients.34 A wide array of formal respite services is available to caregivers of family members with dementia, including both single-service (e.g., in-home respite, adult day service, overnight respite) and multi-component programs (e.g., combination of counseling, in-home, day treatment).35 Surveys of caregivers indicate that they appreciate time away from caregiving.36 Among other positive benefits are reduction in isolation,36 decreased stress, time for more enjoyable activities, and time to attend to personal needs such as healthcare and other family matters.
Experimental evaluations of respite interventions, however, have resulted in mixed findings. Lawton et al.37 reported that caregivers who were provided with respite maintained their relative at home significantly longer, on average 22 days over a 12-month period, and reported higher satisfaction, but not improved mental health or feelings of burden, compared with a group who were not provided with respite. However, only about half (58%) of the participants randomly assigned to receive respite actually utilized the service.
In another large demonstration project (n=642 caregivers), Montgomery and Borgatta38 initially reported negative findings. However, approximately one-third of participants did not use any of the services offered by the intervention. On reanalysis of these data, eliminating those who failed to use services, a significant negative relationship emerged between amount of respite used and time to placement in a nursing home.39 Deimling40 critically reviewed the literature on respite and noted that amount of respite service used by families is not always well documented. Montgomery and Borgatta38 also noted that respite is used inconsistently in early stages of dementia, when demands are low, and more consistently in later stages of caregiving, when demands and burden are greatest.
Caregiver burden is used as an outcome in many caregiver-intervention studies. Knight and colleagues41 and others25 have suggested that modest results may be due to the insensitivity of the outcome instrument (i.e., caregiver burden) to change. Others have suggested that many of the published studies have considerable methodological weaknesses that limit validity of findings.29,30 Pusey and Richards29 recommended several strategies to increase rigor, including increased sample size, random assignment, blinding of raters, targeting specific populations (e.g., spousal vs. adult children), and reduction of response biases that are associated with self-report measures. The present study takes into account many (e.g., sensitive outcomes, random assignment, targeting spousal caregivers, and use of physiological outcomes) but not all of these recommendations.
Study Rationale
Taken together, the literature suggests that caregivers not only state a need and desire for respite interventions, but that these interventions may provide benefit and relief from caregiving, particularly for those who need and have the opportunity to use this service. Although many studies have examined the efficacy of respite by use of standardized measures of depression, burden, and strain (yielding modest results), few, if any, have examined the physiological indicators of stress as an outcome. This area of research is important because previous work suggests that a mismatch between care given and respite received (suggesting caregiver "vulnerability") is related to increased peripheral markers of sympathetic nervous system activation.22
The goal of this study was to determine whether providing in-home respite was associated with a reduction in both psychological and physiological indicators of stress in spousal caregivers of patients with AD, particularly those caregivers who were classed as vulnerable on the basis of being required to provide care for most of the day without much relief.
We chose to use in-home respite because of a survey of our caregivers that indicated an overwhelming preference for in-home respite services. Out-of-home services were perceived as problematic because transportation may be unavailable; patients may be resistant to leaving the home; and patients may be agitated by the upheaval of changing environments throughout the day. In-home respite eliminates many of these perceived problems and may increase adherence to the intervention. Also, several studies have suggested that in-home respite results in improvements in mood,42,43 reduced distress,44 and decreased time spent in caregiving activities.45 Finally, using in-home respite alone allows us to determine how useful a simple, single service is for reducing both psychological and physiological indicators of stress. We hypothesized that at the end of 1 month, the psychological and physiological indicators of stress for vulnerable caregivers who received respite would be significantly reduced.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Procedures
Once eligible participants were identified and informed and had consented, appointments were scheduled in their homes to perform the assessment. Each assessment consisted of two visits: 1) a comprehensive interview, and 2) a physiological assessment, including experimental stressor tasks. All participants completed a baseline interview during the first visit that addressed their general physical and psychological health, the severity of the spouse's dementia, the amount and type of assistance that the AD patient required, the amount of respite received from formal and informal sources, satisfaction with such respite, as well as an inventory of other stressful life circumstances and difficulties. The second visit was scheduled within a week of the initial interview.
All participants then underwent a baseline experimental stress procedure during the second visit. Measurements were made under similar conditions for each of the participants (i.e., they were tested at similar times during the day, and all participants were asked to refrain from caffeine use the day before and day of testing) in order to minimize extraneous factors that might alter catecholamine data.
Physiological assessment consisted of: 1) continuous blood pressure and pulse monitoring via blood pressure cuff on the finger (Finapres, Ohmeda; Madison, WI); and 2) repeated blood sampling for norepinephrine and epinephrine. The experimental stressor tasks were designed to probe the reactivity of the SAM system, the notion being that the altered setpoint of a physiological system may be revealed better from measurement of response to a stressor probe than from basal measurements only. After catheter placement for blood-drawing and a rest/acclimatization period of 15 minutes, a 10-minute baseline began. Blood pressure was monitored every minute during the baseline and speech tasks. At the end of the resting baseline, blood was sampled. Caregivers were then presented with instructions for one of the psychological stressors in counter-balanced order. Blood pressure and heart rate were monitored continuously. Blood samples for epinephrine and norepinephrine were gathered after each speech task.
Stressor tasks.
In the first stressor task, the participant was asked to rehearse, then verbalize a response to an accusation of shoplifting. The participant was given the following situation: "You are stopped at a local department store and accused of stealing a belt that you purchased there the previous week. You are to tell the store manager why you were detained erroneously." A 3-minute period was given to allow the participant to prepare the following five points to be included in the speech: 1) Tell the manager your side of the story. 2) Tell the manager what the security guard did wrong. 3) How can you prove that you did not steal the belt? 4) What should happen to the security guard for the mistake? 5) Summarize your points. After the preparation phase, the tape recorder was conspicuously turned on, and the subject spoke into the microphone. If subjects stopped talking before the end of 3 minutes, they were reminded to continue, if only to summarize and reiterate the main points of the talk. At the end of the 3-minute speech, the tape recorder was turned off, and the subject was asked to rest for 5 minutes. A slightly different version of the task was used for the repeat testing, involving standing up for oneself against a disreputable automobile sales and repair shop.
The second psychological stressor is designed to be specific to caregiving. Once again, there were 3-minute preparation and 3-minute talking phases. Participants were asked to prepare a speech on the most difficult caregiving situation they had to face in the past 2 weeks. As before, at the end of the 3-minute preparation, the tape recorder was turned on, and the caregiver was asked to speak into the microphone.
Vulnerability classification.
The vulnerability classification was based on responses to an interview that probed two dimensions: "How many hours per day does your relative require you to care for him/her?" and "How often do you get respite?" Respite included both formal service and informal supports from family and friends to relieve the caregiver from all or part of caregiving responsibility.
We classified as vulnerable those caregivers who responded that they were required to provide care for their relative more than 12 hours per day, every day, and who, at the same time, had received in-home respite (meaning formal or informal relief from caregiving duties) less than once per month over the past 6-months. The intra-class correlation (ICC) of caregiver classifications (i.e., vulnerable vs. non-vulnerable) shows stability over a 6-week period (ICC=0.98). In terms of the validity of this classification, vulnerable caregivers reported greater levels of distress on the Neuropsychiatric Inventory Caregiver Distress Scale (NPI-D),46 indicating that this classification does reflect caregiver-relevant stress (Table 1). The NPI-D was developed to assess the impact of neuropsychiatric symptoms in AD patients on caregiver distress. Also, vulnerable caregivers were caring for relatives with higher levels of cognitive impairment (based on the Clinical Dementia Rating Scale47 (Table 1). Finally, validity of our classification method is also suggested by previously documented differences between vulnerable and non-vulnerable caregiver groups on some biological measures (e.g., CD62L T-lymphocytes) that are known to be sensitive to stress.23
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2[1]=3.92; p=0.05).
Respite intervention.
After the baseline was complete, both vulnerable and non-vulnerable caregivers were randomly assigned with a table of random numbers to take part in either a respite or non-respite (passive observation) condition.
Caregivers were distributed among four groups as follows: Vulnerable/Respite (n=16); Vulnerable/Non-Respite (n=11); Non-Vulnerable/Respite (n=16; and Non-Vulnerable/Non-Respite (n=12). One of the investigators informed participants of their group assignment.
For those assigned the respite condition, the intervention consisted of 10 days of in-home help (up to 6 hours per day) for the caregiver over a 2-week period. During that time, caregivers had the choice of leaving the home or doing chores, hobbies, or the activity of their choice. In-home help consisted of a professional respite provider who attended to the needs of the patient, but did not engage in unrelated activities such as housework. All professional providers were certified home health aides trained at the George Glenner Alzheimer's Disease Center in the management of AD patients. On average, vulnerable caregivers tended to utilize most of the 60 hours of respite care offered (mean=56.53 hours; standard deviation [SD]: 9.23), whereas non-vulnerable caregivers used approximately half of the respite care hours offered (mean=30.25; SD=27.68). There were, in fact, five non-vulnerable caregivers assigned to receive respite who did not utilize it. Without these five cases, the non-vulnerable caregivers utilized a similar number of hours of respite care (mean=51.86; SD: 9.87) compared with the vulnerable caregivers.
Data were collected at three time-points: baseline (before the beginning of the respite intervention), between Days 7 and 9 of the intervention, and at 1-month post-respite. We elected to analyze baseline and 1-month data in order to examine the enduring effects of the intervention and to allow time for psychological and physiological effects to emerge. This approach was suggested by Cooke and colleagues,25 who noted that caregiver interventions may require a delay before effects become apparent.
Measures
Sociodemographics.
Interviewers gathered information on age, gender, education, financial status, and occupation of the caregivers. Self-reported medical morbidity data were also collected.
Mental health.
Caregivers' mental health was evaluated with two instruments, the Structured Interview Guide for the Hamilton Depression and Anxiety Scales48 and the Brief Symptom Inventory from which the Global Severity Index was computed.49
Catecholamines.
Measurement of catecholamines (e.g., epinephrine and norepinephrine) provides an index of peripheral nervous system activation. Emotional distress is one common trigger of catecholamine secretion. Epinephrine and norepinephrine have both excitatory (e.g., increased rate and force of heart muscle contraction; vasoconstriction) and inhibitory effects (e.g., reduction in digestive system action).
The excitatory effects are of particular interest with respect to cardiovascular health. To measure plasma catecholamine levels, we used a catechol-O-methyltransferase (COMT)-based radioenzymatic assay with a preconcentration step that extracted catecholamines from 1 ml of plasma and concentrated them in 0.1 ml of dilute acid. The assay is 10 times as sensitive as earlier methods. The assay procedure concentrated catecholamines from plasma with 81% efficiency; it also removed components of plasma such as Ca2+ that inhibit the COMT assay. Thus, 1 ng of epinephrine in plasma generated 20,500 cpm of labeled metanephrine in the traditional assay, but, by this procedure, the epinephrine generated 36,750 cpm. The recovery of standard from various plasma samples by the standard assay had a coefficient of variation of 19.6%, whereas this newer assay decreased the coefficient of variation to 6.5%.50
Blood pressure and heart rate.
Beat-to-beat blood pressure was measured with a Finapres noninvasive finger cuff blood pressure monitor. The hand was kept at the level of the heart to control for hydrostatic differences and was also covered with a small blanket to keep it sufficiently warm so that peripheral vasoconstriction did not introduce artifact; considerable data have accumulated relating to conditions for its valid use under precisely controlled circumstances.51,52 Heart rate was measured by attaching an ECG electrode on the right shoulder, on the left anterior axillary line at the 10th intercostal space, and in the right lower quadrant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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For epinephrine, analyses revealed a three-way interaction between Vulnerability (vulnerable versus non-vulnerable), Respite status (respite versus no respite), and Time (pre- versus post-respite; F[1,51]=5.77; p=0.02). As seen in Figure 1, the interaction reflects a lowering of epinephrine in the vulnerable caregivers who received respite, versus a rise in epinephrine in vulnerable caregivers who did not receive respite. Also, there was the expected effect of experimental stressor task, indicating that both speech procedures raised plasma epinephrine significantly (F[2, 102]=9.08; p<0.001). With respect to norepinephrine, there was also a significant effect of stressor task (F[2, 102]=57.08; p<0.001), but no effect of respite. Descriptive statistics for untransformed epinephrine and norepinephrine values before and after treatment are presented in Table 2.
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Psychological Symptoms
Symptoms of depression and anxiety were also investigated in relation to provision of respite in vulnerable and non-vulnerable caregivers. The groups (Respite versus Non-Respite; Vulnerable versus Non-Vulnerable) did not differ significantly at baseline. A 2 (Respite status) x 2 (Time) x 3 (experimental Stressor condition) mixed-model ANOVA did not yield significant main or interaction effects. Therefore, the intervention did not serve to reduce symptoms of depression or anxiety among vulnerable and non-vulnerable caregivers of patients with dementia. Psychological distress was also measured with the Global Severity Index from the Brief Symptom Inventory.47 A 2 (Respite status) x 2 (Time) x 3 (experimental Stressor condition) mixed-model ANOVA did not yield any significant main or interaction effects.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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These results may be viewed as preliminary evidence that sympatho-adrenal-medullary activation, which may be evident in that subgroup of caregivers who experience a severe mismatch between demand and resources available, may derive physiological benefit from interventions that help to restore a more favorable balance between demand and relief.
A growing body of literature suggests that at least some caregivers experience both physiological and medical changes that may be stress-mediated. For example, caregivers have been noted to experience more medical hospitalizations and medical symptoms than age-matched control subjects.16
The mechanisms underlying these caregiving-related changes remain imperfectly understood. Two of the major "integrative" stress-response physiological systems are the hypothalamic-pituitary-adrenal (HPA) and the sympatho-adrenal-medullary (SAM) systems. Our previous work has suggested that the SAM system is altered under conditions of caregiving stress. For example, neuropeptide Y, a neurotransmitter present in peripheral sympathetic nerves and co-localized with catecholamines, was found in increased concentrations in plasma of AD caregivers versus age-matched control subjects.53 Neuropeptide Y is thought to play a role in longer-term control of blood pressure and may also have immuno-regulatory effects.
Also, in a long-term follow-up of spouses who were caregiving for AD patients, we noted a tendency for the caregivers to develop mild hypertension.15 This may be important because both hypertension and indices of sympatho-adrenal-medullary arousal are predictors of cardiovascular morbidity such as myocardial infarction and stroke.54–57
Along these lines, we noted that caregivers experiencing increased life events stressors showed changes in hemostatic factors that are typically associated with hyper-coagulable states. For example, plasma concentration of one factor—D-dimer—was highest in caregivers who reported excessive stressful life events.58 Increases in such coaguability markers have previously been linked to cardiovascular disease.59,60
Because, in our society, caregivers tend to be elderly persons (generally spouses) of AD patients, it would not be surprising to find that such caregivers may have acquired cardiovascular risk factors even before they became caregivers. In such individuals, it would be plausible to speculate that the added stress of caregiving might then further enhance the likelihood of a future cardiovascular event. In support of this possibility, we noted recently that pro-coagulation factor response of a group of our caregivers who performed an experimental stressor task (verbally responding to a scenario about accusations of being a thief or speaking about a particularly stressful caregiving event) was augmented in those caregivers with background histories of cardiovascular disease.58 There was also a positive significant correlation between degree of change in some of these pro-coagulation factors (e.g., the von Willebrand Factor) and change in plasma epinephrine concentration during the acute stressor task.58 Taken together, these observations are consistent with the notion that the stress of caregiving can produce, in some caregivers, a state of heightened sympatho-adrenal-medullary activity, some of whose indicators include increased activities of neuropeptide Y and plasma epinephrine. This SAM arousal, if chronic, might lay the groundwork for development of longer-standing increases in blood pressure or, among those already susceptible to cardiovascular disease, may create alterations in the physiological milieu (e.g., clotting factors) that could lead directly to cardiovascular events.
The SAM system may also influence immune events. Earlier, we noted that reductions in natural killer-cell activity in AD caregivers were related to increases in circulating neuropeptide Y.53
More recently, we noted that reduction in a subset of immune cells—the L-selectin–negative CD8 and CD4 subsets—was found in vulnerable caregivers.61 In these subjects, the degree of depletion of L-selectin–negative lymphocytes was correlated with circulating plasma epinephrine concentration. These lymphocytes, which are members of the TH1 line of cells, are probably important in mounting inflammatory responses to injury. Of interest, Glaser and Kiecolt-Glaser found that caregivers mounted poorer immune responses to viral challenges13 and evidenced poorer rates of wound healing.14 In more recent work, this group demonstrated that in women with high-perceived stress, high stress was related to lower levels of two cytokines, interleukin 1-
and interleukin 8, at wound sites, and that such women had poorer wound healing.62 The expression of these cytokines is probably mediated by the TH1 line of cells, such as the CD8/L62–lymphocytes that we examined in Mills et al.22 Since the reduction in these cells was correlated with rise in plasma epinephrine, these observations provide additional indirect evidence that arousal of the SAM system might also be involved in impaired immune response in some stressed caregivers. Also, one recent report noted enhancement of retroviral replication in persons with HIV infection who had high sympathetic nervous system activity.63
In view of the above, it seems likely that the SAM system may be pivotal, at least, in increasing cardiovascular risk, and possibly in inducing poorer immune response under conditions of chronic stress, such as AD caregiving. If so, then efforts at interventions that can demonstrate reduction in SAM arousal as a consequence would be of clear importance. Thus, our observation that a simple, 2-week respite intervention was associated with reduction in circulating epinephrine, suggesting reduced SAM arousal in our vulnerable caregivers who received it, certainly merits confirmation and follow-up. In particular, it would be useful to determine whether certain other markers that putatively are influenced by the SAM system and which may be important in morbidity, are also altered as the result of an intervention. For example, it would be useful to determine whether changes in cellular adhesion molecules, coagulation factors, or HPA-axis functioning could be modified by such interventions. If positive associations were noted, then further research on the more specific mechanisms would be worthwhile.
In terms of mechanisms, the present study failed to detect improvements in mood measures in relation to the respite intervention. Perhaps the lack of change reflected the low level of self-reported anxiety and depression in our groups. Be that as it may, it seems unlikely that anxiety and depression were major mediators of epinephrine reduction related to respite in this study. Future studies might consider other psychological variables (e.g., improvements in cognitive appraisal) as possible mediators of intervention-associated change in SAM arousal.
In a preliminary study such as this, it is important to acknowledge several limitations. First, the sample size was limited, raising questions about representativeness. We cannot be certain that selection factors might not have influenced results in ways that are difficult to predict. To the extent such problems might be present, there may be limitations to the generalizability to larger, more diverse samples. Second, we could not consider all possible covariates. Furthermore, larger studies will need to explore more systematically effects such as those of various medications.
In summary, the current study provides preliminary evidence that a simple respite intervention may be useful in reducing sympatho-adrenal-medullary arousal in a subgroup of caregivers who may be considered vulnerable to deleterious health outcomes by virtue of being placed under unusually burdensome caregiving circumstances in the context of inadequate social support.
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ACKNOWLEDGMENTS |
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This work was supported by a National Institute on Aging grant (R01 AG15301-12) awarded to Igor Grant, M.D., P.I.
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This article has been cited by other articles:
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  K. Aschbacher, R. von Kanel, P. J. Mills, S. Hong, S. K. Roepke, B. T. Mausbach, T. L. Patterson, M. G. Ziegler, J. E. Dimsdale, S. Ancoli-Israel, et al. Combination of Caregiving Stress and Hormone Replacement Therapy is Associated With Prolonged Platelet Activation to Acute Stress Among Postmenopausal Women Psychosom Med, November 1, 2007; 69(9): 910 - 917. [Abstract] [Full Text] [PDF]
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 K. Aschbacher, R. von Kanel, J. E. Dimsdale, T. L. Patterson, P. J. Mills, B. T. Mausbach, M. A. Allison, S. Ancoli-Israel, and I. Grant Dementia Severity of the Care Receiver Predicts Procoagulant Response in Alzheimer Caregivers Am J Geriatr Psychiatry, August 1, 2006; 14(8): 694 - 703. [Abstract] [Full Text] [PDF]
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K. Aschbacher, T. L. Patterson, R. von Kanel, J. E. Dimsdale, P. J. Mills, K. A. Adler, S. Ancoli-Israel, and I. Grant Coping Processes and Hemostatic Reactivity to Acute Stress in Dementia Caregivers Psychosom Med, November 1, 2005; 67(6): 964 - 971. [Abstract] [Full Text] [PDF]
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B. T. Mausbach, J. E. Dimsdale, M. G. Ziegler, P. J. Mills, S. Ancoli-Israel, T. L. Patterson, and I. Grant Depressive Symptoms Predict Norepinephrine Response to a Psychological Stressor Task in Alzheimer's Caregivers Psychosom Med, July 1, 2005; 67(4): 638 - 642. [Abstract] [Full Text] [PDF]
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L. Redwine, P. J. Mills, M. Sada, J. Dimsdale, T. Patterson, and I. Grant Differential Immune Cell Chemotaxis Responses to Acute Psychological Stress in Alzheimer Caregivers Compared to Non-caregiver Controls Psychosom Med, September 1, 2004; 66(5): 770 - 775. [Abstract] [Full Text] [PDF]
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P. J. Mills, K. A. Adler, J. E. Dimsdale, C. J. Perez, M. G. Ziegler, S. Ancoli-Israel, T. L. Patterson, and I. Grant Vulnerable Caregivers of Alzheimer Disease Patients Have a Deficit in {beta}2-Adrenergic Receptor Sensitivity and Density Am J Geriatr Psychiatry, June 1, 2004; 12(3): 281 - 286. [Abstract] [Full Text] [PDF]
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P. A. Arean Advances in Psychotherapy for Mental Illness in Late Life Am J Geriatr Psychiatry, February 1, 2003; 11(1): 4 - 6. [Full Text] [PDF]
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