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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
JAMA. Author manuscript; available in PMC 2012 March 15.
Published in final edited form as:
PMCID: PMC3304539
NIHMSID: NIHMS355747

Caregiving Burden, Stress, and Health Effects Among Family Caregivers of Adult Cancer Patients

Abstract

Unlike professional caregivers such as physicians and nurses, informal caregivers, typically family members or friends, provide care to individuals with a variety of conditions including advanced age, dementia, and cancer. This experience is commonly perceived as a chronic stressor, and caregivers often experience negative psychological, behavioral, and physiological effects on their daily lives and health. In this report, we describe the experience of a 53-yearold woman who is the sole caregiver for her husband, who has acute myelogenous leukemia and was undergoing allogeneic hematopoietic stem cell transplantation. During his intense and unpredictable course, the caregiver's burden is complex and complicated by multiple competing priorities. Because caregivers are often faced with multiple concurrent stressful events and extended, unrelenting stress, they may experience negative health effects, mediated in part by immune and autonomic dysregulation. Physicians and their interdisciplinary teams are presented daily with individuals providing such care and have opportunity to intervene. This report describes a case that exemplifies caregiving burden and discusses the importance of identifying caregivers at risk of negative health outcomes and intervening to attenuate the stress associated with the caregiving experience.

Case Study

A 56-year-old man with myelodysplastic syndrome transformed into acute myelogenous leukemia with cytogenetic abnormalities presented for a reduced intensity allogeneic matched unrelated-donor hematopoietic stem cell transplantation (HSCT). Prior to HSCT he had multiple unanticipated complications and treatment toxicities from his cytoreductive regimen resulting in a 3 month in-patient hospitalization. The caregiver was his wife of 23 years, a 53-year-old female. She reported a history of arthritis and was 3 years post coronary artery bypass graft surgery following a myocardial infarct. Currently a smoker, she reported that she was trying to quit. The caregiver reported extremely high levels of psychological distress, including anxiety, depression, worry and extreme loneliness, prior to the transplant.

Baseline Factors

The couple's primary residence was in New Jersey, 143 miles from the transplant center, therefore they were required to establish a temporary residence nearby. Because both the patient and caregiver were unemployed due to disability, their income was restricted. Social support was limited to a 20-year-old daughter in college and the caregiver's sister, employed full-time in New Jersey. In addition, the caregiver's elderly mother and aunt depended upon her for assistance, as did her father who resided in a nursing home after becoming disabled following brain surgery.

Course of Treatment

The HSCT initial hospitalization and immediate recovery period was difficult and prolonged, lasting approximately two months. The patient experienced a pericardial effusion, renal failure, pneumonia, and acute Graft versus Host Disease. After the initial hospital discharge, the patient was readmitted twice: once for coughing, diarrhea, and hematuria with clots; and a second time for acute heart failure and sepsis.

Caregiving Challenges

This caregiver had multiple caregiving responsibilities, maintained two residences, subsisted on limited finances, and managed multiple health conditions of her own. Lacking the physical presence of a support system, she shouldered the entire burden of her husband's brief but intense outpatient care including: cleaning, driving, preparing meals, and coordinating medication, oxygen and other treatment-related activities. She struggled to maintain hope for the transplant's success, while living with the constant uncertainty of her husband's survival, a concern that was exacerbated by the sudden death of a close cousin. While she complained little, when asked, she reported severe emotional distress, significant fatigue, sleep impairment, and difficulty maintaining her focus and energy throughout the transplant trajectory.

Background

Family caregivers are essential partners in the delivery of complex health care services and this case exemplifies the associated caregiver burden and stress during cancer treatment. Unlike professional caregivers such as physicians and nurses, informal caregivers, typically family members or friends, provide care to individuals with a variety of conditions, most commonly advanced age, dementia, and cancer1. As more and more evidence suggests that caregiving is deleterious to one's health, increased attention is being paid to the day to day well-being of caregivers2. Compared to non-caregivers, caregivers often experience psychological, behavioral, and physiological effects that can contribute to impaired immune system function and coronary heart disease, and early death35.

The level of burden upon caregivers of cancer patients is greater than the burden experienced by those caring for the elderly and similar to that experienced by caregivers of patients with dementia6. To receive a diagnosis of cancer is recognized as a significant stressor to the patient and family. However, the resultant treatment creates additional fears and challenges, and frequently requires the direct support of a caregiver including: assisting with activities of daily living, administering medications, providing transportation, preparing meals, managing finances, advocating for health care, and providing emotional support. Caregiving is labor intensive, with approximately one-quarter of those caring for cancer patients spending in excess of 40 hours a week providing these services to family or friends1. The level of care required by the care recipient is a major factor that influences the caregiver's life and health effects. Caregivers of cancer patients providing higher levels of support are more likely to report negative outcomes, less likely to be effective partners in the patient's care, and are more likely to postpone their own health care needs.

While cancer patients in general report high symptom severity resulting in a greater need for support from the health care team7, one of the most complex cancer treatments, allogeneic hematopoietic stem cell transplantation (HSCT), is particularly burdensome. Even an uncomplicated or reduced intensity allogeneic HSCT may require a 2- to 4- week hospitalization, followed by 3- to 4- months of intense outpatient management. Allogeneic HSCT recipients are often debilitated and frequently experience complications and other treatment-related toxicities that result in multiple hospital readmissions8. For this reason, the caregiver and her husband were required to establish a residence near the transplant center. Without a caregiver, transplant options may be limited and survival shortened9, 10. While this potentially curative treatment provides hope, it also carries a 30% mortality rate within the first year11. As a result, caregivers experience layer upon layer of stress, as the burden of caring (often exclusively) for their sick loved ones, separated from their own support systems, while balancing other life responsibilities, threatens to overwhelm them12.

Presenting Signs and Symptoms of Stress

As evident in the case study, the most obvious signs and symptoms of caregiving stress are often psychological problems, most commonly anxiety, depression, worry and loneliness13. These psychological reactions are related to the caregiver's appraisal of the experience, with those reporting more benefit and deriving more meaning from the experience feeling less stress and reporting better quality of life14. The level of distress reported by many of those caring for someone with cancer can be equal to or greater than that of the cancer patient15, with adult daughters seeming to have the greatest difficulties14. In addition, those reporting higher levels of emotional distress also report more problems with fatigue, sleep impairment and unhealthy behaviors16.

Caregivers of patients with cancer report having to modify their lifestyles to accommodate the care recipient's needs including restricting leisure activity and contact with friends and family13. Thus, at a time when caregivers are most in need of the restorative benefits of relaxation, they have the least amount of time and resources available. Further complicating matters, caregivers of cancer patients prioritize the needs of the patient over their own17, leaving little time for maintaining good nutrition, exercising, and undertaking health evaluations. As a result, caregivers have numerous health related problems, such as sleep disturbances and fatigue, which worsen as the patient's physical function and symptom burden increase18. The symptom burden in HSCT recipients can be significant for weeks to months following the treatment19 and may contribute to the symptoms reported by HSCT caregivers during the survivorship phase20.

Pathogenesis of Health Effects in Caregivers

The experience of caring for an individual undergoing HSCT transplantation is inherently stressful and one's perception of an event plays a large role in the body's response. All stressors activate the hypothalamic-pituitary-adrenal (HPA) axis and the adrenergic sympathetic nervous system (SNS). After exposure to stressful stimuli, the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release adrenocorticotropic hormone (ACTH). ACTH in turn triggers the release of glucocorticoids (cortisol) from the adrenal cortex. At the same time the sympathetic nervous system is activated with release of epinephrine (adrenalin) from the adrenal medulla and norepinephrine from sympathetic nerves. In combination, the molecules released during the stress response have profound effects on the function of most cells and organs throughout the body, including the brain, heart, respiratory system, muscles, skin, liver, gastrointestinal tract and, importantly, the immune system21.

Activation of the acute stress response is life-saving and prepares the organism to avoid impending danger, with enhanced vigilance, focused attention and increased energy. In contrast, chronic stress has negative consequences on health. In chronic stress the healthy `diurnal rhythm' of the HPA axis, with a late evening nadir and a morning peak, is flattened showing instead low morning and elevated afternoon/evening cortisol levels22. This represents a state of physiological “burn-out” that often accompanies psychological burnout. In the early stages of burnout, HPA axis activity is increased. Months later, HPA axis activity decreases. Family caregivers of cancer patients also show autonomic imbalance with a shift towards the sympathetic and away from the parasympathetic tone23, 24, and dementia caregivers, compared to non-caregiving controls, exhibited higher Framingham coronary risk scores largely due to higher blood pressure25. One explanation for this progression may be related to changes in caregivers' psychological coping and expectations, with active coping early and loss of expectations of being able to cope successfully later in the process. More recent studies indicate that dysregulation of circadian rhythm during chronic stress also has an endocrine basis. Thus, even mild elevations in evening cortisol, as occurs in chronic stress, can disrupt the CLOCK gene mechanism of circadian regulation of the HPA axis, resulting in functional hypercortisolism26.

While a single stressful event or multiple events with time to recover between events may not affect health, multiple stressors without adequate recovery time or chronic stressful events as presented in the case study, are likely to increase the risk for illness. `Allostatic load' is the term coined to define the “load” or total burden of multiple stressors27, such as those to which caregivers are exposed on a daily basis. A large allostatic load is a potential mechanism linking caregiving to adverse health outcomes28. Chronic stress, including in caregivers of Alzheimer's patients, has been shown to increase risk for infection 29, 30; decrease take rate of vaccine; slow wound healing30; speed cancer growth via beta-adrenergic mechanisms that stimulate angiogenesis31; and speed chromosomal aging as indicated by telomere shortening32. Stress does not cause these conditions, but can foster them through the effects of stress hormones and neurotransmitters on disease processes and immune responses. On the other hand, a blunted HPA axis response and functional glucocorticoid resistance have been associated with pro-inflammatory states and predispose to autoimmune/inflammatory diseases21, cardiovascular disease33, diabetes and metabolic syndrome, which is characterized by central or abdominal obesity, high blood pressure, elevated cholesterol and insulin resistance34, and depression35.

Evaluating and Managing Stress in Caregivers of Cancer Patients

While stressful events are inevitable, it is possible to identify those at increased risk for negative outcomes, assess the degree to which the caregiver's life and health may be negatively affected, and recommend interventions that could attenuate the negative repercussions of the caregiving experience. Should a patient present for a primary care visit and it is determined that they serve as a caregiver for an individual with cancer; it can rightly be assumed that the caregiver will be affected15. As a component of preventative care, recognizing the challenges and possible effects of caregiving will enhance the plan of care developed between the physician and the patient. However, when a caregiver accompanies a cancer patient for a medical visit, the caregiver may hide or minimize the effects of the caregiving experience in an effort to shield the patient and avoid shifting attention to themselves. In this setting, determining the context of the caregiving experience can begin with an expanded history and physical on the patient that includes the caregiver's assessment.

The caregiver is this case study presented with her husband, and their needs were assessed by the interdisciplinary team including an oncology social worker. This included the knowledge level of the caregiver related to role expectations, the patient care needs or degree of burden, and the presence of competing responsibilities. Brief screening questionnaires can be helpful in a busy clinical environment. Caregivers can complete the questionnaire independently and the responses are easy to interpret by a nurse, social worker or physician providing guidance regarding possible referrals for specialized care. The Distress Thermometer (DT)36 is a single-item self-report measure of distress and includes a list of `problems' creating distress for cancer patients and has been validated in HSCT caregivers 37. In addition, the American Medical Association (AMA) developed the Caregiver Self-Assessment Questionnaire (CASQ)38 to assess caregiver stress and health which was validated as a self-report screening measure for depression in caregivers of patients with dementia 39. The AMA Healthier Life Steps Program's Personal Health Habits Questionnaire assesses key lifestyle behaviors including smoking, use of alcohol, nutrition practices and exercise40. Web-based collection systems such as the Patient Reported Outcomes Measurement Information System (PROMIS)® are now available to both researchers and clinicians, allowing collection of a large variety of outcome data including symptoms commonly prevalent in caregivers of cancer patient such as: depression, anxiety, fatigue, and sleep disturbance41. Two unique functions of PROMIS® are the ability to collect patient outcomes longitudinally, making it possible to follow changes in function over time, as well as the ability to compare patients' outcomes against national norms.

Many well validated psychological questionnaires are sensitive, but are also subjective indicating the need for development of more objective, quantitative measures of allostatic load. In a research setting, a comprehensive assessment of allostatic load or cumulative stress includes psychological measures of stress such as distress, anxiety, and depression; hormonal measures of the HPA axis response (cortisol); physiological measures of the sympathetic and parasympathetic nervous system (BP, HR, heart rate variability (HRV)42, 43 and salivary amylase44; and measures of end-organ effects such as immune system status and chromosomal damage27, 32. Some newer non-invasive methods include cortisol levels in hair 45 and stress and immune biomarkers in eluates from sweat patches46. While many of these approaches show promise, they are not yet applicable in the clinical setting. More research is needed to develop and validate sensitive, non-invasive and quantitative measures of allostatic load and to develop models that predict health outcomes.

The assessment of stress and how it affects the health of family caregivers should be followed by guidance and individualized interventions to attenuate the health consequences. The mere act of assessing and listening to the caregivers' needs communicates empathy which may in itself improve outcomes 47, 48. Offering the patient and caregiver `how to' information regarding patient care, maintenance of family and marital relationships, and the importance of self-care may help caregivers be more prepared and less distressed 49. Community or web-based resources for caregivers are plentiful (www.cc.nih.gov/wecare/resources.html) with a selected few highlighted in Table 1. A growing body of evidence also supports simple stress management practices such as walking, meditating and adopting nutritional changes such as the Mediterranean diet that may help reduce fatigue, improve sleep and reduce the risk of some stress-related illnesses50, 51. Clinicians should remain alert to stress-related symptoms such as elevated blood pressure and heart rate, as well as delayed wound healing or increased frequency of infections. Current evidence may be limited due to single site designs and small sample sizes but multisite studies with a focus on the translation of interventions into practice in addition to studies on caregivers' physical health specifically those who are at high risk for poorer outcomes, will guide the development of cost-effective targeted approaches to care49 Providing this level of care is not without reward, as improving the experiences of caregivers may in itself, provide “greater sustenance and meaning” for the physician48.

Table 1
Caregiver Resources

Case Study Follow-up

The patient expired during his second readmission, within 6 months of beginning the HSCT treatment. His wife then “had to go thru the phases of planning his funeral which I was not prepared for feeling like there was nothing left for me.” She “went through the grieving process like everyone else…just trying to survive”. She had the daunting task of explaining to her sick elderly father that her husband had passed away; four months later he too passed away, only two days before his 90th birthday. Shortly thereafter, she experienced another myocardial infarction and required the placement of a pacemaker.

More recently, financial pressures forced the caregiver to sell her house and downgrade to more affordable housing, and her cardiovascular disease continues to require careful management. On a happier note, her daughter, now 22 years old, is expecting the family's first grandchild.

Recognizing the psychological, behavioral, and physiological effects of caring for a loved one with cancer is an opportunity for primary prevention. A common barrier in primary prevention is access; attending to a population without overt need for health care services. In this population, the potentially affected individuals are entering offices and health care agencies on a regular basis with a cancer patient. Caregivers of patients with cancer are essential partners in the quality care we strive to deliver to our patients. How preventive services such as screening, education and referrals are systematically incorporated into our health care system is beyond the scope of this paper but worthy of future attention.

Table 2
Brief Depression and Stress Screening Tools for Caregivers

Acknowledgments

The authors would like to acknowledge the family featured in the case study. The authors would also like to acknowledge and thank Leslie Wehrlen, RN, BSN, OCN®; Alyson Ross, RN, MS; Stephen Klagholz, BS, Gwenyth Wallen, RN, PhD; Clare Hastings, RN, PhD, FAAN at the NIH Clinical Center for their support of this program of research and manuscript.

Footnotes

The authors have no conflicts of interest relevant to this publication.

References

1. NAC [Accessed 8/20/10];Caregiving in the U.S. 2009 http://www.caregiving.org/data/Caregiving_in_the_US_2009_full_report.pdf.
2. Vitaliano PP, Zhang JP, Scanlan JM. Is caregiving hazardous to one's physical health? A meta-analysis. Psychol. Bull. 2003 Nov;129(6):946–972. [PubMed]
3. Gouin JP, Hantsoo L, Kiecolt-Glaser JK. Immune dysregulation and chronic stress among older adults: a review. Neuroimmunomodulation. 2008;15(4–6):251–259. [PMC free article] [PubMed]
4. Lee S, Colditz GA, Berkman LF, Kawachi I. Caregiving and risk of coronary heart disease in U.S. women: A prospective study. Am. J. Prev. Med. 2003;24(2):113–119. [PubMed]
5. Schulz R, Beach SR. Caregiving as a risk factor for mortality - The caregiver health effects study. Jama-J Am Med Assoc. 1999 Dec 15;282(23):2215–2219. [PubMed]
6. Kim Y, Schulz R. Family caregivers' strains: comparative analysis of cancer caregiving with dementia, diabetes, and frail elderly caregiving. J. Aging Health. 2008 Aug;20(5):483–503. [PubMed]
7. Kurtz ME, Kurtz JC, Given CW, Given BA. Depression and physical health among family caregivers of geriatric patients with cancer--a longitudinal view. Med Sci Monit. 2004 Aug;10(8):CR447–456. [PubMed]
8. Grant M, Cooke L, Bhatia S, Forman SJ. Discharge and unscheduled readmissions of adult patients undergoing hematopoietic stem cell transplantation: Implications for developing nursing interventions. Oncol. Nurs. Forum. 2005;32(1):E1–E8. [PubMed]
9. Foster LW, McLellan LJ, Rybicki LA, Sassano DA, Hsu A, Bolwell BJ. Survival of patients who have undergone allogeneic bone marrow transplantation: The relative importance of in-hospital lay care-partner support. J Psychosoc Oncol. 2004;22(2):1–20.
10. Frey P, Stinson T, Siston A, et al. Lack of caregivers limits use of outpatient hematopoietic stem cell transplant program. Bone Marrow Transplant. 2002;30(11):741–748. [PubMed]
11. CIBMTR Annual Report. [web page] [Accessed 11/22/11];Reference Center, Slides Reports, Summary Slides. 2009 Available at: http://www.cibmtr.org/ReferenceCenter/SlidesReports/SummarySlides/Pages/Index.aspx.
12. Beattie S, Lebel S. The experience of caregivers of hematological cancer patients undergoing a hematopoietic stem cell transplant: a comprehensive literature review. Psycho-Oncol. 2011;20(11):1137–1150. [PubMed]
13. Stenberg U, Ruland CM, Miaskowski C. Review of the literature on the effects of caring for a patient with cancer. Psycho-Oncol. 2010;19(10):1013–1025. [PubMed]
14. Kim Y, Schulz R, Carver CS. Benefit-finding in the cancer caregiving experience. Psychosom. Med. 2007 Apr;69(3):283–291. [PubMed]
15. Hodges LJ, Humphris GM, Macfarlane G. A meta-analytic investigation of the relationship between the psychological distress of cancer patients and their carers. Soc. Sci. Med. 2005;60(1):1–12. [PubMed]
16. Swore Fletcher B, Dodd M. Symptom experience of family caregivers of patients with cancer. Oncol. Nurs. Forum. 2008;35(2):E23–E44. [PubMed]
17. Williams LA. Whatever it takes: Informal caregiving dynamics in blood and marrow transplantation. Oncol. Nurs. Forum. 2007;34(2):379–387. [PubMed]
18. Palos GR, Mendoza TR, Liao KP, et al. Caregiver symptom burden: the risk of caring for an underserved patient with advanced cancer. Cancer. 2011 Mar 1;117(5):1070–1079. [PMC free article] [PubMed]
19. Bevans MF, Mitchell SA, Marden S. The symptom experience in the first 100 days following allogeneic hematopoietic stem cell transplantation (HSCT) Support. Care Cancer. 2008;16(11):1243–1254. [PMC free article] [PubMed]
20. Bishop MM, Beaumont JL, Hahn EA, et al. Late effects of cancer and hematopoietic stem-cell transplantation on spouses or partners compared with survivors and survivor-matched controls. J. Clin. Oncol. 2007;25(11):1403–1411. [PubMed]
21. Sternberg EM. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat. Rev. Immunol. 2006;6(4):318–328. [PMC free article] [PubMed]
22. Heim C, Ehlert U, Hellhammer DH. The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders. Psychoneuroendocrinology. 2000;25(1):1–35. [PubMed]
23. Lucini D, Cannone V, Malacarne M, et al. Evidence of autonomic dysregulation in otherwise healthy cancer caregivers: a possible link with health hazard. Eur. J. Cancer. 2008 Nov;44(16):2437–2443. [PubMed]
24. Rohleder N, Marin TJ, Ma R, Miller GE. Biologic Cost of Caring for a Cancer Patient: Dysregulation of Pro- and Anti-Inflammatory Signaling Pathways. J. Clin. Oncol. 2009 Jun 20;27(18):2909–2915. [PubMed]
25. von Kanel R, Mausbach BT, Patterson TL, et al. Increased Framingham coronary heart disease risk score in dementia caregivers relative to non-caregiving controls. Gerontology. 2008;54(3):131–137. [PubMed]
26. Nader N, Chrousos GP, Kino T. Interactions of the circadian CLOCK system and the HPA axis. Trends Endocrin Met. 2010 May;21(5):277–286. [PMC free article] [PubMed]
27. Juster RP, McEwen BS, Lupien SJ. Allostatic load biomarkers of chronic stress and impact on health and cognition. Neurosci. Biobehav. Rev. 2010 Sep;35(1):2–16. [PubMed]
28. Roepke SK, Mausbach BT, Patterson TL, et al. Effects of Alzheimer caregiving on allostatic load. J Health Psychol. 2011 Jan;16(1):58–69. [PMC free article] [PubMed]
29. Cohen S, Tyrrell DA, Smith AP. Psychological stress and susceptibility to the common cold. N. Engl. J. Med. 1991;325(9):606–612. [PubMed]
30. Glaser R, Kiecolt-Glaser JK. Stress-induced immune dysfunction: implications for health. Nat. Rev. Immunol. 2005;5(3):243–251. [PubMed]
31. Armaiz-Pena GN, Lutgendorf SK, Cole SW, Sood AK. Neuroendocrine modulation of cancer progression. Brain. Behav. Immun. 2009;23(1):10–15. [PMC free article] [PubMed]
32. Epel ES, Blackburn EH, Lin J, et al. Accelerated telomere shortening in response to life stress. Proc. Natl. Acad. Sci. U. S. A. 2004;101(49):17312–17315. [PubMed]
33. Nijm J, Jonasson L. Inflammation and cortisol response in coronary artery disease. Ann. Med. 2009;41(3):224–233. [PubMed]
34. Bjorntorp P, Rosmond R. Neuroendocrine abnormalities in visceral obesity. Int. J. Obes. 2000 Jun;24:S80–S85. [PubMed]
35. Pace TWW, Hu F, Miller AH. Cytokine-effects on glucocorticoid receptor function: Relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain Behavior and Immunity. 2007 Jan;21(1):9–19. [PMC free article] [PubMed]
36. NCCN [Accessed 11/21/11];Distress Management - NCCN Guidelines for Supportive Care. 2011 http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
37. Bevans M, Wehrlen L, Prachenko O, Soeken K, Zabora J, Wallen GR. Distress screening in allogeneic hematopoietic stem cell (HSCT) caregivers and patients. Psycho-Oncol. 2011 [PMC free article] [PubMed]
39. Epstein-Lubow G, Gaudiano BA, Hinckley M, Salloway S, Miller IW. Evidence for the validity of the American Medical Association's caregiver self-assessment questionnaire as a screening measure for depression. J. Am. Geriatr. Soc. 2010 Feb;58(2):387–388. [PubMed]
40. AMA [Accessed 11/14/11];Healthier Life Steps Questionnaire - American Medical Association. 2008 http://www.ama-assn.org/resources/doc/public-health/hl_questionnaire.pdf.
41. PROMIS-NIH [Accessed 05/20/11];Patient Reported Outcomes Measurement Information System (PROMIS) 2011 http://www.nihpromis.org/.
42. Lederbogen F, Kuhner C, Kirschbaum C, et al. Salivary cortisol in a middle-aged community sample: results from 990 men and women of the KORA-F3 Augsburg study. Eur. J. Endocrinol. 2010 Sep;163(3):443–451. [PubMed]
43. Thayer JF, Sternberg EM. Neural aspects of immunomodulation: focus on the vagus nerve. Brain. Behav. Immun. 2010 Nov;24(8):1223–1228. [PMC free article] [PubMed]
44. Strahler J, Mueller A, Rosenloecher F, Kirschbaum C, Rohleder N. Salivary alpha-amylase stress reactivity across different age groups. Psychophysiology. 2010 May;47(3):587–595. [PubMed]
45. Steudte S, Stalder T, Dettenborn L, et al. Decreased hair cortisol concentrations in generalised anxiety disorder. Psychiatry Res. 2011 Apr 30;186(2–3):310–314. [PubMed]
46. Cizza G, Marques AH, Eskandari F, et al. Elevated neuroimmune biomarkers in sweat patches and plasma of premenopausal women with major depressive disorder in remission: the POWER study. Biol. Psychiatry. 2008;64(10):907–911. [PMC free article] [PubMed]
47. Emanuel EJ, Fairclough DL, Slutsman J, Emanuel LL. Understanding economic and other burdens of terminal illness: the experience of patients and their caregivers. Ann. Intern. Med. 2000 Mar 21;132(6):451–459. [PubMed]
48. Rabow MW, Hauser JM, Adams J. Supporting family caregivers at the end of life: “they don't know what they don't know” JAMA. 2004 Jan 28;291(4):483–491. [PubMed]
49. Northouse LL, Katapodi MC, Song L, Zhang L, Mood DW. Interventions with family caregivers of cancer patients: meta-analysis of randomized trials. CA. Cancer J. Clin. 2010 Sep-Oct;60(5):317–339. [PMC free article] [PubMed]
50. Jacobs TL, Epel ES, Lin J, et al. Intensive meditation training, immune cell telomerase activity, and psychological mediators. Psychoneuroendocrinology. 2011 Jun;36(5):664–681. [PubMed]
51. Sofi F, Abbate R, Gensini GF, Casini A. Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis. Am. J. Clin. Nutr. 2010 Nov;92(5):1189–1196. [PubMed]