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Type D Personality, Th-1 Cytokine Levels and Cytomegalovirus Antigenemia in Patients Undergoing Allogeneic Hematopoietic...

Permanent Link: http://ufdc.ufl.edu/UFE0041704/00001

Material Information

Title: Type D Personality, Th-1 Cytokine Levels and Cytomegalovirus Antigenemia in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplant
Physical Description: 1 online resource (40 p.)
Language: english
Creator: Patidar, Seema
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: bone, cancer, cytokines, cytomegalovirus, hsct, type
Clinical and Health Psychology -- Dissertations, Academic -- UF
Genre: Psychology thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Cytomegalovirus (CMV) is a latent Herpes virus that may cause life-threatening illness in immune-compromised individuals. T-helper cell type 1 (Th1) cytokines, such as Interleukin-12, Interferon-gamma, and Tumor Necrosis Factor-alpha, facilitate cell-mediated immunity and immune-surveillance of latent CMV. Psychosocial factors, including stress and negative mood states, are associated with poorer CMV immune-surveillance. However, no research has examined psychoneuroimmunologic relations in Hematopoietic Stem Cell Transplant (HSCT) recipients at risk for CMV disease. The present study examined relationships among social inhibition/negative expressivity (?Type D personality? traits), Th1 cytokines, and CMV reactivation in HSCT. Eighty-six participants (M age=46.83 yrs; SD=11.83yrs) completed the Millon Behavioral Medicine Diagnostic (MBMD) before HSCT. Th1 cytokine levels were examined in sera at HSCT Days 0 and 28. Participants were followed for development of CMV antigenemia (ag) for 1 year. Using regression analyses, Type D personality was not associated with Th1 cytokines or greater odds of CMVag. However, greater Introversion, specifically, was associated with higher Day 28 TNF-alpha (a CMVag risk factor in HSCT), and this relationship was mediated by higher Day 0 IL-12. These findings suggest Introversion is associated with cytokines that may increase risk for CMV disease in HSCT. Future research should attempt to replicate and expand upon these findings in a larger, more diverse, HSCT sample.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Seema Patidar.
Thesis: Thesis (M.S.)--University of Florida, 2010.
Local: Adviser: Pereira, Deidre B.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0041704:00001

Permanent Link: http://ufdc.ufl.edu/UFE0041704/00001

Material Information

Title: Type D Personality, Th-1 Cytokine Levels and Cytomegalovirus Antigenemia in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplant
Physical Description: 1 online resource (40 p.)
Language: english
Creator: Patidar, Seema
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: bone, cancer, cytokines, cytomegalovirus, hsct, type
Clinical and Health Psychology -- Dissertations, Academic -- UF
Genre: Psychology thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Cytomegalovirus (CMV) is a latent Herpes virus that may cause life-threatening illness in immune-compromised individuals. T-helper cell type 1 (Th1) cytokines, such as Interleukin-12, Interferon-gamma, and Tumor Necrosis Factor-alpha, facilitate cell-mediated immunity and immune-surveillance of latent CMV. Psychosocial factors, including stress and negative mood states, are associated with poorer CMV immune-surveillance. However, no research has examined psychoneuroimmunologic relations in Hematopoietic Stem Cell Transplant (HSCT) recipients at risk for CMV disease. The present study examined relationships among social inhibition/negative expressivity (?Type D personality? traits), Th1 cytokines, and CMV reactivation in HSCT. Eighty-six participants (M age=46.83 yrs; SD=11.83yrs) completed the Millon Behavioral Medicine Diagnostic (MBMD) before HSCT. Th1 cytokine levels were examined in sera at HSCT Days 0 and 28. Participants were followed for development of CMV antigenemia (ag) for 1 year. Using regression analyses, Type D personality was not associated with Th1 cytokines or greater odds of CMVag. However, greater Introversion, specifically, was associated with higher Day 28 TNF-alpha (a CMVag risk factor in HSCT), and this relationship was mediated by higher Day 0 IL-12. These findings suggest Introversion is associated with cytokines that may increase risk for CMV disease in HSCT. Future research should attempt to replicate and expand upon these findings in a larger, more diverse, HSCT sample.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Seema Patidar.
Thesis: Thesis (M.S.)--University of Florida, 2010.
Local: Adviser: Pereira, Deidre B.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0041704:00001


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1 TYPE D PERSONALITY, TH 1 CYTOKINE LEVELS AND CYTOMEGALOVIRUS ANTIGENEMIA IN PATIENTS UNDERGOING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT B y SEEMA M PATIDAR A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY O F FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2010

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2 2010 Seema M Patidar

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3 Dedicated to my family

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4 ACKNOWLEDGMENTS I would like to thank Deidre Pereira and my lab mates for their support and a researcher and I greatly appreciate her eagerness to sha re her knowledge and experience with me. I thank Dr. Vijay Redd y, the principal investigator, for allowing me to be a part of this study; collaborating with him has been a rewarding experience. I would also like to thank Dr. Michael Antoni at the University of Miami for his advice I acknowledge the members of my supe rvisory committee, Dr. Vonetta Dodson, Dr. Patricia Durning, and Dr. Sheila Eyberg. Additionally, I would like to thank my family and friends for their continued encouragement and support through this process. Finally, I greatly appreciate the participati on of all the patients in this study and wish them the best

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 7 LIST OF FIGURES ................................ ................................ ................................ .......... 8 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .... 11 HSCT ................................ ................................ ................................ ...................... 11 Cytomegalovirus ................................ ................................ ................................ ..... 11 Th 1 Cytokines and the Immune Response ................................ ............................ 13 Psychosocial Factors ................................ ................................ .............................. 14 Type D Personality ................................ ................................ ................................ 16 Current Study ................................ ................................ ................................ .......... 18 2 METHODS ................................ ................................ ................................ .............. 19 Design ................................ ................................ ................................ ..................... 19 Participants ................................ ................................ ................................ ............. 19 Preliminary Study Procedures (Parent Study) ................................ ........................ 20 Screening and Enrollment ................................ ................................ ................ 20 Health Assessment ................................ ................................ .......................... 20 Longitudinal Immunologic Assessment ................................ ................................ ... 20 Detection of CMVag ................................ ................................ ......................... 20 Quantitation of Cytokine Levels ................................ ................................ ........ 21 Pre HSCT Psyc hology Clinic Evaluation ................................ ................................ 21 Diagnostic Interview ................................ ................................ ......................... 21 Psychological Testing ................................ ................................ ....................... 22 Statistical Analyses ................................ ................................ ................................ 23 3 RESULTS ................................ ................................ ................................ ............... 26 Sample Characteristics ................................ ................................ ........................... 26 CMVag and Cytokine Levels ................................ ................................ ................... 26 Associations Among Control Variables, Cytokines, and CMVag ............................ 26 MBMD Subscales ................................ ................................ ................................ ... 27 Creation of the Type D Personality Variable ................................ ........................... 27 Associations among Type D Personality, Cytokines, and CMVag .......................... 27 Exploratory Analyses ................................ ................................ .............................. 28

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6 4 DISCUSSION ................................ ................................ ................................ ......... 32 Primary Aims ................................ ................................ ................................ .......... 32 Study Limitations and Future Directions ................................ ................................ 34 LIST OF REFERENCES ................................ ................................ ............................... 36 BIOGRAPHICAL SKETCH ................................ ................................ ............................ 40

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7 LIST OF TABLES Table page 2 1 Normality data for cytokine variables ................................ ................................ .. 25 3 1 Comparison of con tinuous demographic and biological variables ...................... 29 3 2 Comparison of categorical demographic and biological variables ...................... 29 3 3 Presen ce of latent CMV and development of CMVag ................................ ........ 29 3 4 Type D personality and odds of developing CMVag ................................ ........... 29 3 5 Association between type D personality and Th 1 cytokine levels ...................... 30 3 6 Association between MBMD subscales and Th 1 cytokine levels ...................... 30 3 7 MBMD subscales and odds of developing CMVag ................................ ............. 30

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8 LIST OF FIGURES Figure page 3 1 Survival functions for type D personality and non type D personality ................. 31 3 2 Mediation model and significant mediation results ................................ ............. 31

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9 Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of t he Requirements for the Degree of Master of Science TYPE D PERSONALITY, TH 1 CYTOKINE LEVELS AND CYTOMEGALOVIRUS ANTIGENEMIA IN PATIENTS UNDERGOING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT By Seema M Patidar May 2010 Chair: Deidre B Pereira Ma jor: Psychology Cytomegalovirus (CMV) is a latent Herpes virus that may cause life threatening illness in immune compromised individuals. T helper cell type 1 (Th1) cytokines such as Interleukin 12 (IL 12), Interferon and Tum or Necrosis Fa ctor alpha facilitate cell mediated immunity and immune surveillance of latent CMV. Psychosocial factors, including stress and negative mood states, are associated with poorer CMV immune surveillance. However, no research has examined psychoneuro immunologic relations in Hematopoietic Stem Cell Transplant ( HSCT ) recipients at risk for CMV disease. The present study examined relationships among CMV reactivatio n in HSCT. Eighty six participant s ( M age=46.83 yrs; SD =11.83yrs) completed the Millon Behavioral Medicine Diagnostic (MBMD) before HSCT. Th1 cytokine levels were examined in sera at HSCT Days 0 and 28. Participant s were followed for development of CMV antigenemia (ag) for 1 year. Using regression analyses Type D personality was not associated with Th1 cytokines or greater odds of CMVag. However, greater Introversion, specifically, was associated with higher Day 28

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10 and this relationship was mediated by higher Day 0 IL 12 These findings suggest Introversion is associated with cytokines that may increase risk for CMV disease in HSCT. Future research should attempt to replicate and expand upon these findings in a lar ger, more diverse, HSCT sample.

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11 CHAPTER 1 INTRODUCTION HSCT Hematopoietic stem cell transplants (HSCT) are commonly performed in the treatment of leukemias and lymphomas. Approximately 35,000 of these transplants are performed each year throughout the w orld (Bishop, Welsh, Coons and Wingard, 2001). Allogeneic HSCT is performed when the patient receives stem cells from a related or (National Cancer Institute [NCI] 2009) Prior to tr ansplant, allogeneic HSCT recipients undergo intensive chemotherapy conditioning regimens in preparation to receive their transplant. Conditioning is intended to weaken rejection as th However, conditioning regimens also leave HSCT recipients immuno compromised, putting them at higher risk of post transplant infection until their immune system is reconstituted (NCI, 2009) Post HSCT, recipients are e xpected to attain engraftment and continued immune reconstitution. These are often attained around 4 weeks post HSCT, at which time discharge from the hospital is indicated. After discharge patients have frequent follow up visits to assess immune recons titution, determine presence of infection and monitor prophylactic medical regimens (Bishop, 2001) Cytomegalovirus Cytomegalovirus (CMV) is a latent Herpes virus (Human Herpes virus 5 [ HHV 5 ]) which can cause life threatening illness when reactivated in immune compromised individuals, such as HSCT recipients (Humar, et al. 1998; Torres, et al. 2006) CMV is

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12 present in bodily fluids (i.e. blood and saliva) and can be transmitted easily. Approximately 50% to 80% of people in the United States have contra cted CMV by the age of 40 (C enter for D isease C ontrol and Prevention [CDC] 2009). Once contracted, CMV remains in the body in latent form and can be reactivated at times of immune suppression. Patients undergoing allogeneic HSCT are at increased risk for experiencing CMV reactivation, but not all of these patients will experience CMV reactivation (Osarogiagbon, Defor, Weisdorf, M., Erice, and Weisdorf, J., 2000) Latent CMV can be detected and presenc e of latent CMV may put HSCT recipients at increased risk of developing CMV antig e nemia (ag) (CDC, 2010) CMVag is detected a number of different ways, including a pp65 antigenemia assay which utilizes immune flourescence to detect levels of CMV antigen in blood and is commonly used in immune compromised patients (Reddy, Meier Kreische, Greene, Schold, and Wingard, 2005) Incidence rates of CMV reactivation in HSCT recipients vary from 15% to 50%, with greatest risk for allogeneic HSCT recipients (Osarogia gbon, 2000) Allogeneic HSCT recipients at risk for CMVag are commonly treated with prophylactic medication for the first 100 days post HSCT to prevent reactivation However, patients are still at risk of CMVag after this critical period of immuno compromi se (Humar et al. 1998 ; Gluckman, Traineau, Devergi, Esperouc Bourdeau and Hirsch, 1992 ). Reactivation of CMV can lead to pneumonia, hepatitis, colitis and other opportunistic diseases ( Reinke, Prosch, Kern and Volk, 1999 ) Patients experiencing active graft versus host disease (GVHD) are at additional risk of critical subsequent disease, as their immune system is additionally suppressed to encourage acceptance of

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13 the host graft. Once CMV has been reactivated, it can demonstrate episodic or prolonged pro gression and this reactivation has been associated with higher mortality rates in HSCT recipients ( Gluckman, 1992; Osarogiagbon, 2000 ) Th 1 Cytokines and the Immune Response Post HSCT immune suppression primarily impairs cell mediated immunity, which fac ilitates immuno surveillance of latent CMV (Humar et al., 1998) T helper cell type 1 (Th 1) cytokines are inflammatory markers involved in cell mediated immunity and the Th 1 cytokines, such as Interleukin 12 ( IL 12 ), In terferon gamma ( IFN signaling throughout the immune system. Many Th 1 cytokines also serve to stimulate the production of other cytokines; for example, IL 12 proliferation can stimulate incre ased cell mediated production of and ( Ibelgauft, 2008). Therefore, c ytokine levels may be assessed in the peripheral blood in order to monitor the progression of immune reconstitution and the presence of infection, such as CM V ag Th 1 cytokines are associated with important clinical outcomes among HSCT recipients. For instance, IL 12 may have potential anti tumor effects, because of its effects on T cells and other c ytokines One study has shown that low Th 1 cytokine profile transplant populations (Essa et al., 2009). In support of this, Reddy and colleagues (2005) demonstrated that high pre HSCT IL 12 levels were associated with higher post HSCT IL 12 levels and improved survival, without relapse or increased risk for GVHD in 134 HSCT recipients 1 cytokine, may also have important clinical implications in HSCT recipients. For example, higher post HSCT levels were

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14 associated with greater risk of CMVag (Padron, Schold, Dallas, Levine and Reddy, 2008) Although Th competence and immune reconstitution, some research suggests that the presence of CMV may cause increase s in IFN levels This may account for the counter intuitive findings of Reddy et al. (2005). Other research has shown may be the primary contribu tor to negative disease outcomes. For example, higher post HSCT levels were associated with greater risk of developing CMVag, as these patients developed CMVag earlier and had increased likelihood of post may be a key marker in the development of life threatening viral infection, s pecifically CMVag (Reddy, 2005). Psychosocial Factors The HSCT experience is often very stressful for patients, particularly immediately prior to HSCT when patients are preparing for a series of conditioning treatments of sub lethal intensity (Bishop, 2001 ) During the HSCT process, p atients often report feeling significant distress, depression (Grulke, Larbig, Kachele, and Bailer, 2008), and anxiety, among other concerns (Bishop, 2001) Importantly, t he se emotional correlates of HSCT have been associated with negative health behaviors and negative clinical outcomes ( Andrykowski, Brady, and Henslee Downey, 1994; Hoodin and Weber, 2003 ) For instance, depression and defiance have been associated with lower survival rates among patients undergoing HSCT (And rykowski, 1994), a relationship that may be reflective of the bio behavioral model of tumor biology described by Antoni et al. (2006). According to this model, negative emotions may be associated with poorer clinical outcomes in cancer via the activation of the HPA and ANS stress systems and the downstream effects of this activation on antitumor immunity. Cytokines are key

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15 components in cell to a threat, such as acute infection or chroni c stress. Therefore, HSCT recipients experiencing significant levels of psychosocial distress may experience immune compromise, which may be reflected by poor Th 1 cytokine profiles, due to dysregulation of the HPA and ANS systems (Antoni et al., 2006). Of note, no published research has examined the association between psychosocial factors and specific pathophysiologic outcomes in HSCT, such as CMVag or CMV associated disease. Psychosocial factors, including stress and negative mood states, have been asso ciated with both poorer immuno surveillance over latent CMV infection (Glaser Kiecolt Glaser, Speicher and Holiday, 1985; Glaser and Kiecolt Glaser 19 97 ) and lower post HSCT survival rates (Hoodin and Weber, 2004). Thus, the possibility exists that psyc hosocial factors may be associated with lower survival via poor immuno surveillance over latent viral infections. Furthermore, t he ability to predict psychosocial consequences would allow intervention prior to transplant tha t could improve patient outcom e (Bishop, 2001). Research suggests that psychosocial intervention, such as stress reduction techniques, could modulate immunity and improve patient outcome, but more research demonstrating change in patient outcome is needed (Pennebaker, Colder and Sharp, 1990; van Rood, Bogaards, Goulmy and van Houwelingen, 1993). Identifying which patients are at risk of psychosocial distress prior to transplant would allow those patients to be targeted for intervention, potentially mediating the odds of post HSCT infect ion and promoting survival in HSCT recipients.

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16 Type D Personality Personality is another important psychosocial factor in the cancer experience, although research in personality and health populations has a controversial history. Initially, Type A persona lity or the Type A Behavior Pattern, was considered the associated with the development of coronary heart disease However, later findings suggest that specific personality traits that comprise Type A personality such as anger and hostility, may be the critical underlying fact ors explaining this association ( Sanderman and Ranchor, 1997). Also, Type B personality is often considered the anti type A personality, as these patients were not likely to develop coronary heart disease and have opposing personality traits to Type A patients. (Thomas, 1986) Type C personality, associated with passive coping and suppressed expression, has been researched as a risk factor for the development of canc er. In fact, Type C personality was once to date includes significant results for and against the association between Type C personality and cancer outcomes including both incidence and progression of disease (Sanderman and Ranchor, 1997) Consequently, t here has been much controversy regarding th e potential role of personality in cancer ; however, more recently, psychoneuroimmunology researchers have sugge sted that personality may explain individual differences in immune response and may generally influence patient perspectives toward cancer and treatment (Lutgendorf, 2003; Segerstrom, 2003). Recently a Type D personality has been described, which is marked by social inhibition and negative affectivity. More specifically, p atients with Type D personality are characterized by a tendency to inhibit emotions or behaviors in

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17 order to evade social criticism (social inhibition) and to experience negative emotions (negative affectivity) (D enollet, 1999). Both negative affect and inhibition have been independently associated with negative health outcomes (Pennebaker 1990). Studies have shown that Type D personalit y, which may have a genetic component, is present in 1 3 3 3 % of the general pop ulation and 20 53% in t he heart disease population (Kupper, Gidron, Winter and Denollet, 2003; Mols, Holterhues, Nijsten, and vandePoll Franse, in press). Patients exhibiting Type D personality are likely to have higher levels of chronic stress, higher mor tality rates, and increased anxiety and depression (Denollet, 1999; Pedersen, 2009). Type D personality was first identified and researched in the heart disease population Denollet and colleagues found Type D personality to be an independent pr edictor of chronic heart failure, as well as poor quality of life and increased mortality in the heart disease population (Denollet, 1999; Pedersen, 2009) With regard to heart failure patients and subsequent cytokine function, Type D personality has also been assoc iated with elevated mortality (Denollet et al., 2003; Denollet, Vrints and Conraads, 2008). Studies have suggested that the association between Type D personality and negative health outcomes may be mediated by eleva ted cortisol levels stemming from dysregulation of the HPA axis (Molloy, Perkins Porras, Strike, and Steptoe 2008). Few published studies have examined the relationships among Type D personality, psychosocial outcomes, and clinical outcomes in cancer. A recent study in melanoma survivors determined that patients exhibiting Type D personality reported significantly worse mental health, overall health, and less vitality (Mols, in press).

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18 Furthermore, Denollet et al. (1998) demonstrated that Type D persona lity men with heart failure were more likely to develop cancer. These studies suggest that more extensive examination of Type D personality in cancer is warranted. Current Study The current study examined the relationships among Type D personality (soc ial inhibition/negative expressivity), Th 1 cytokine levels, and CMVag in allogeneic HSCT recipients. The first aim was to determine if Type D personality was associated with CMV reactivation. Based on the literature, patients exhibiting Type D personality were expected to have greater odds of developing CMVag within 1 year post HSCT. The second aim was to examine the Th 1 profile of Type D patients, and the presence of Type D personality is hypothesized to be indicative of poor Th 1 cytokine profile. Poor Th 1 cytokine profiles were identified by lower IL 12 levels on the day of transplant and higher 28).The third aim of the study was to examine a mediational model to determine if poor Th 1 cytokine profiles significantly mediated the relationship between Type D personality and CMVag. Additional exploratory analyses examined the association between poor Th 1 cytokine profiles/increased risk of developing CMVag and the individual personality traits comprising Type D personality.

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19 CHAPTER 2 METHODS Design The current study was a secondary data analysis of two, linked data sets. The first data set, collected by Reddy and colleagues, included immune and clinical outcome data for 211 HSCT recipients recruited/enrolled from 1999 2004 at the University of Florida. The design of this parent study was non experimental and longitudinal. The second data set involved the creation of a new database comprised of data abstracted from routine pre HSCT psychological evaluations conducted at the Psychology Clinic at the University of Florida H ealth Science Center. These two data sets were then linked by patient name and a de identified dataset was formed containing pre HSCT psychological evaluation data, longitudinal immune data, and longitudinal clinical outcome data on 186 patients. This stu dy was approved and monitored by the Institutional Review Board at the University of Florida Health Science Center. Participants Participants for the present study were 86 of the original 186 participants who (a) old, (b) underwent allogene ic transplant and (c) completed the Millon Behavioral Medicine Diagnostic (MBMD) (Millon, 2001) in its entirety during a routine pre HSCT psychological evaluation at the Psychology Clinic. Participants with incomplete cytokine profiles were excluded from i ndividual analyses. The present sample ( M age = 47 years old, SD = 12 years) included 40 men and 46 women undergoing allogeneic HSCT for hematologic cancers. Fifty eight of the participants had myeloablative conditioning and 28 had non myeloablative con ditioning, with the majority of transplants involving infusion of peripheral blood stem cells. The

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20 sample was comprised of primarily White, non Hispanic patients (N=74) with a variety of diagnosis. Acute myeloid leukemia was the most common disease (N=29, 33.7%), followed by acute lymphoblastic leukemia (N=16, 18.6%), chronic myeloid leukemia (N= 10, 11.6%), and myelodysplastic syndrome (N= 9, 10.5%). Other diseases included multiple myeloma (N=7, 8.1%) and non l ess common hematologic malignancy types (N=9, 10.5%). Preliminary Study Procedures (Parent Study) Screening and Enrollment Between 1999 and 2004, all HSCT recipients attended a routine meeting with a research nurse prior to transplant in order to provide them with the opportunity to enroll in any ongoing clinical trials at the transplant center. After review of the informed consent form in this meeting, patients were enrolled in the parent study; a HIPAA Waiver of Consent was attained to collect follow up health related data from medical records. Health Assessment Prior to HSCT, all patients and donors underwent a complete medical evaluation, including detection of CMV antibody, or latent CMV. Additionally, disease type (original cancer diagnosis), lev el of risk (high or low), conditioning regimen (myeloablative or non myeloablative), stem cell source (peripheral blood, bone marrow, or umbilical cord blood) and donor relationship to patient (related or unrelated) were verified and included as potential control variables in the current study. Longitudinal Immunologic Assessment Detection of CMVag As a part of the parent study, participants were followed for the development of CMVag for one year following transplant. Post HSCT CMVag was detected via ro utine

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21 pp65 antigenemia assay of blood collected while inpatient or at routine post HSCT medical visits. Primary outcomes for the current study include the presence or absence of CMVag during one year post HSCT and the day of development of CMVag (if appli cable). Quantitation of Cytokine Levels As part of the parent study, IL (the day of transplant) and Day 28 (commonly the last day of the inpatient period of stay). Cytokine levels (pictograms per millili ter) were determined using ELISA assays. In the current study, IL examined as outcomes and possible mediators of a significant relationship between Type D personality and CMVag. Pre HSCT Psy chology Clinic Evaluation Diagnostic Interview As part of the pre HSCT evaluation, patients underwent a routine psychological evaluation to assess current psychological, social and behavioral well being. At this visit, psychologists assessed patient motiv ation for HSCT and their cognitive ability to provide informed consent, as well as any other potential psychosocial concerns or barriers to successful HSCT (Rodrigue, 2001). During this evaluation, history of substance use (e.g. tobacco, alcohol, marijuan a), ongoing mental health disorder, history of medical adherence, presence of social support/caregiver (e.g. marital status), and basic demographic data (e.g. age, gender, ethnicity were assessed. For the present study, these data were abstracted from psy chology clinic charts and were considered potential variables that could confound a significant relationship between Type D personality and CMVag.

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22 Psychological Testing Patients were administered the MBMD to supplement the findings of the diagnostic int erview. The MBMD is a self report measure with strong reliability and validity. It has been normed across various health populations and is routinely used with the cancer population; this measure is administered to all HSCT recipients who undergo assessme nts in the UF Psychology Clinic. The MBMD consists of 165 true or false items, which constitute 7 domains (Response Patterns, Negative Health Habits, Psychiatric Indications, Coping Styles, Stress Moderators, Treatment Prognostics and Management Guides). T disease progression or treatment regimen (Millon, 2001). In consultation with the creators of the MBMD and guided by existing Type D research, a Type D construct was created using three Coping Sty le MBMD subscales: Introversive (high values suggest Type D personality), Inhibited (high values suggest Type D personality), and Sociable (low values suggest Type D personality) The Introversive subscale assesses the frequency and degree to which a per son exhibits a lack of e motion and demonstrates vague if any, communication of their concerns Patients who attain high Introversive scores are generally withdrawn and approximately 16% of medical patients have been characterized by this style of function ing The Inhibited subscale assesses how comfortable a patient is with other people and if they readily express their concerns. Patients with high scores on this subscale can be very sensitive and often isolate themselves; approximately 15% of patients are considered to have this coping style. Sociable is a subscale that assesses the degree to which a person discusses relevant concerns or views with high scores corresponding to a

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23 person who seeks out and enjoys social interaction; approximately 15% of pati ents are expected to demonstrate this method of coping (Millon, 2001). Cluster analysis was utilized to operationalize the Type D personality construct using the above MBMD subscales. distinguish cluster s. Two distinct groups formed representing the presence or absence of Type D personality traits This dichotomous variable, reflecting presence or absence of Type D personality, was used as the primary predictor in all analyses Statistical Analyses Chi s quare tests and t tests were utilized to determine if the 86 individuals included in the present sample were significantly different from the remaining 100 in the parent study in age, gender, ethnicity (non white Hispanic, or other), marital status, tobacc o use, alcohol use, marijuana use, presence of CMVag, number of days to CMVag, disease type, disease risk, conditioning type, stem cell source, and type of donor. In order to identify bio behavioral factors that may confound a significant relationship bet ween Type D personality traits and CMVag, the previously mentioned variables were also examined as potential control variables using independent samples t tests and Chi Square analyses. One way ANOVA and Pearson correlations were used to determine if these potential control variables were significantly associated with post HSCT Th 1 cytokine levels D escriptive statistics, including normality statistics, were examined for each cytokine variable, see Table 2 1. For each cytokine, skewness and kurtosis value to the range of values, and each variable had large standard deviation values (all>100). Therefore, all cytokine variables were statistically transformed {log[cytokine(pg/mL)+5]} to improve normality for the use parametric statistics.

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24 All subsequent analyses were adjusted for relevant control variables. Cox Regression was performed to determine if the presence of Type D personality was significantly associated with post HSCT deve lopment of CMVag Hierarchical linear regressions were conducted to determine if Type D personality was associated with individual cytokine levels above and beyond relevant control variables, and to determine if any cytokine values mediated a significant T ype D CMVag relationship. In the event that Type D personality was unassociated with cytokines and CMVag, exploratory analyses were planned. These analyses examined the relationship between the three individual Type D MBMD subscales and cytokine levels and development of CMVag.

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25 Table 2 1 Normality d ata for cytokine variables Variable name N M (SD) Median Range Skewness Kurtosis IL12 Day 0 74 119.55 (236.59) 10.50 0 1231 9.95 15.28 IL12 Day 28 52 113.62 (251.36) 17.00 1 1238 10.85 20.68 IFN 82 62.80 (174.01) 3.00 0 978 13.75 26.90 70 24.31 (104.26) 1.00 0 824 24.07 91.80

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26 CHAPTER 3 RESULTS Sample Characteristics A comparison of the 86 patients in the present sample and the 100 excluded patients from the larger study d emonstrated no significant difference between groups with regard to age, sex, HSCT type, relationship to donor, graft source, presence of CMVag, or days to CMVag. However, as expected given the inclusion of only allogeneic HSCT patients in the present stu dy, the present sample included more HSCT recipients with high disease risk than the larger sample, 2 = 12.69, p <.001 ( Full comparison in Table s 3 1 and 3 2 ). CMVag and Cytokine Levels Prior to transplant, HSCT recipient and respective donor CMV antibody titres revealed 35 recipient positive, donor positive pairs; 7 recipient positive, donor negative pairs; 24 recipient negative, donor positive pairs; and 18 recipient negative, donor negative pairs, see T able 3 3 Results of pp65 antigenemia assays identified CMVag in 39 of the 86 patients within one year. Most patients developed CMVag within 100 days post HSCT ( M = 67.92 SD =70.84). Post HSCT Th 1 cytokine levels were variable among patients Levels of IL 12 at Day 0 ( M =119.55, SD =236.59), IL 12 at Day 28 ( M =113.62, SD =251.36), IFN at Day 28 ( M =62.80, SD =174.01) and TNF at Day 28 ( M =24.31, SD =14.26) we re all relatively low and variable, as many factors contribute to immune reconstitution post HSCT. Associations Among Control Variables, Cytokines, and CMVag White, non Hispanic race/ethnicity was significantly associated with the development of CMVag ( 2 (1, N = 85) = 4.77, p= 03)

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27 Day 28 ( F (1,69)=8.80, p= .004) and IL 12 at Days 0 and 28 (Day 0: F (1,73)=6.46, p=.013; Day 28: F (1,51)=4.62, p= .036) Thus, White, non Hispanic race/ethnicity was adjusted for in subsequent analyses with CMVag as the outcome variable, as well as in 12 as outcome variables. In addition, high d isease risk was significantly associated with F (1,81)=6.98, p= .01) and higher IL 12 at Day 0 ( F (1,73)=6 .98, p= .004) Thus, high disease risk was also controlled for in 12 at Day 0 as the outcome variables. MBMD Subscales Three MBMD subscales were identified as likely contributors to Type D personality in the current sa mple: the Introversive subscale ( M =36.67, SD =23.25), the Inhibited subscale ( M =34.97, SD =24.17) and the Sociable subscale ( M =56.20, SD =20.01). Type D personality was expected to be marked by high levels of Introversive and Inhibited coping, combined with l ow Sociable scores. Patients attained a wide range of scores on each subscale, suggesting that this is a fairly diverse sample. Creation of the Type D Personality Variable Cluster Analysis using Euclidian distance was conducted with the three MBMD subscale s (Introversive, Inhibited, and Sociable). A clustering algorithm minimized the most distinction between clusters occurring when two clusters were identified. The two di stinct clusters indicate the presence of Type D personality in the sample : Cluster 1 = Type D personality ( N =47); Cluster 2 = No n Type D personality ( N =39). Association s among Type D Personality, Cytokines, and CMVag Cox Regression analyses revealed that a fter controlling for race/ethnicity, Type D personality was not significantly associated with greater odds of developing CMVag by

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28 one year (Table 3 4). Figure 3 1 demonstrates the unadjusted Kaplan Meier survival curves for CMVag for Type D and non Type D patients. One way ANOVAs showed that Type D personality was not associated with Th1 cytokine levels in this sample after covarying for relevant controls (Table 3 5). Given these null findings, mediation could not be examined in this sample. Exploratory Analyses Exploratory analyses found that greater Introversion was associated with higher levels of Day 0 IL p= .002) after adjusting for relevant controls. Neither Inhibited nor Sociable scale scores was significantly associated with Th 1 cytokine levels (Table 3 6). Higher values on the Sociable subscale were associated with significantly greater hazards for the development of CMVag, HR = 1.02, p = .04; however, this HR indicates that h igh Sociable scores increased the hazards of developing CMVag by only 2% (Table 3 7). Given that Introversion was associated with both higher Day 0 IL 12 and higher Day 28 linear regression analysis was performed to examine whether Day 0 IL controlling for I L p=.004, indicating that higher Day 0 IL 12 levels mediated the relationship between 2).

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29 Table 3 1 Comparison of conti nuous demographic and biological variables Variable name Study sample mean ( SD ) Total sample mean ( SD ) t df p value Age 46.83 (11.83) 46.75 (13.22) 0.04 183.0 0.97 Days to CMVag 67.92 (70.84) 40.21 (17.86) 2.22 42.6 0.03 likely significant due to o utliers (+365 days) Table 3 2 Comparison of categorical demographic and biological variables Variable name 2 df p value Sex 1.24 1 0.27 Marital status 3.63 3 0.30 Race/ethnicity 0.91 1 0.34 Alcohol use 0.14 2 0.93 Tobacco use 4.24 2 0.12 Marijuana use 3.47 2 0.18 Disease type 17.13 8 0.03 Disease risk 12.69 1 0.00 ** Conditioning type 0.10 1 0.75 Ste m cell source 0.76 2 0.68 Donor type 0.76 1 0.38 CMVag 1.17 1 0.28 *indicates significant at p<.05; **indicates significant at p<.01 Table 3 3 Presence of latent CMV and development of CMVag Latent CMV Number of each combination Number of patients de veloping CMVag Recipient Donor Neg Neg 18 2 Neg Pos 24 11 Pos Pos 35 24 Pos Neg 7 2 Total number of patients developing CMVag 39 Table 3 4 Type D personality and odds of developing CMVag Variable name HR p value Race/ethnicity 0. 78 0. 54 Ty pe D personality 1.10 0.77

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30 Table 3 5 Association between type D personality and Th 1 cytokine levels Post Variable name p value Race/ethnicity 0.34 0.004 ** Type D personality 0.02 0.87 Post Variable name p value Disease risk 0.28 0.01 Type D personality 0.01 0.90 HSCT IL12 Variable name p value Race/ethnicity 0.28 0.01 Disease risk 0.33 0.004 ** Type D personality 0.02 0.85 Post HSCT IL12 Variable name p value Race/ethnicity 0 .31 0.02 Type D personality 0.23 0.10 *indicates significant at p<.05; **indicates significant at p<.01 Table 3 6 Association between MBMD subscales and Th 1 cy t okine levels Variable name Post HSCT Post HSCT TNF HSCT IL12 Post HSCT IL12 In troversive 0.22 0.34 0.33 0.24 Inhibited 0.06 0.03 0.04 0.20 Sociable 0.18 0.07 0.01 0.04 Note Table values are Standardized Beta weights yielded by regressing Th 1 cytokines on individual MBMD subscales; *indicates significa nt at p<.01 Table 3 7 MBMD subscales and odds of developing CMVag Variable name HR p Introversive 0.99 0.12 Inhibited 1.00 0.68 Sociable 1.02 0.04 *indicates significant at p<.05

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31 Figure 3 1. Survival functions for type D personality and non t ype D personality Figure 3 2. Mediation model and significant mediation results

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32 CHAPTER 4 DISCUSSION Primary Aims The current study suggests that Type D personality, as operationalized by three MBMD subscales, may not be significantly associate d with greater odds of post HSCT development of CMVag. Additionally, Type D personality did not predict Th 1 cytokine profiles favoring poor antitumor immunity. However, when examining the MBMD subscales individually, higher Sociable scores were associated with 2% greater odds of developing CMVag, a value that is unlikely to be clinically relevant. Additionally, HSCT recipients with higher Introversive scores on the MBMD had higher IL 12 levels on the HSC T. Furthermore, higher IL 12 at Day 0 mediated the relationship between Introversion and post These findings suggest that while higher IL 12 at HSCT Day 0 may reduce risk for disease/progression, relapse, or GVHD (Reddy et al., 2005), it may ha ve concomitant This finding highlights the importance of examining relationships between psychosocial factors and sets of related cytokines, rather than with simply o ne cytokine. However, these findings remain tentative and suggest that these relationships should be examined in a larger sample. This future research should attempt to eliminate or control for known influences on CMVag. For instance, immunosuppressant regimens for GVHD are known to increase risk of developing CMVag (Gluckman, 1992; Osarogiagbon, 2000). Therefore the potential post HSCT effects of IL explored in a larger sample that can more fully evaluate other potential con tributors to this relationship.

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33 CMVag or Type D personality, supporting very recent research by Essa et al. (2009) suggesting that CMV may bypass, or interfere, with pathways by suggesting that it may not be involved in the Introversion post this sample. However, future research should examine whether other post HSCT IFN antiviral immunity relationships in HSCT. In this study, an introversive coping style was considered reflective of Type D personality, as it is characterized by difficulty expre ssing emotion and internalizing thoughts. While most research considers introversion to be a negative behavioral health indicator (Canada, Fawzy, N. and Fawzy, F., 2005), some research suggests that introverts may actually have more robust responses to beh avioral conditioning processes that may lead to better immune responses (McKenna, Zevon, Corn and Rounds, 1999). This possibility should be examined in future research, as well. Type D personality focuses in on the synergistic effect of Inhibition and Ne gative Affect. Inhibited coping style was not associated with any outcomes. However, there is some item overlap on the MBMD Introversive and Inhibited subscales. This suggests that it may be worthwhile to examine the role of inhibited coping styles on p ost HSCT infection vulnerability using other measures. Also, while age was not significantly associated with outcomes in this sample, it may be worth consideration in future research. Extraversion scores have been found to decline with age, while cancer r

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34 both increase with age. Age may be a co factor in any psychosocial antiviral immunity relationships, highlighting the complexity of examining PNI relationships in a seriously medically ill sample of pri marily older adults. Study Limitations and Future Directions The current study does possess some notable limitations. The study was a s econdary data analysis and thus limited by the methodological characteristics of the parent study. The sample size was modest, but similar in size to that of other research in this population (Grulke, 2008; Reddy, 2005). Also, many patients were unable to provide complete data, including blood samples for complete cytokine profiles, and not all patients completed the MBMD psychosocial data significantly impedes the generalizability of the current study, as similar relationships may not emerge using other measures of Type D personality. Due to the small sample size, the powe r of the current study is limited, and additional research is needed in a larger, more diverse sample to confirm the current findings. Additional c oncern s commonly associated with research on this pop ulation are the various control variables that may be as sociated with treatment and disease progression. Potentially confounding variables include patient demographic, biological, and other unmeasured psychosocial variables (e.g., socio economic status, medication regimens, graft source, social support). Due to power constraints and data limitations, all potentially significant control variables could not be included in the statistical analyses Another important consideration of this study is the measurement of Type D personality. Both t he Inhibited and Introversive subscale s were utilized, but these scales have a reasonable degree of overlap, which could have influenced how patients were

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35 clustered; the Sociable score may have had less weight in the clustering process as a result. Although the prevalence of Type D personality in the current sample (45%) was within the expected range for a chronically ill population (20 53%), our Type D personality variable may have lacked sufficient construct validity. The current study did not utilize the Type D Scale 14 (DS 14), a valid and reliable 14 item scale, which is now commonly used to identify Type D personality in other populations (Denollet, 2005). Furthermore, a dichotomous Type D construct was created using cluster analysis, but a recent taxometric analysis s uggests that Type D personality may exist along a continuum and should ideally be assessed on a Likert scale (Ferguson et al., 2009). Future research on Type D personality in this population should be conducted with the DS 14 to accurately evaluate Type D personality and cancer outcomes, including the potential role of cytokines in the relationship. Based on the lack of literature on Type D personality in the cancer population, there is need to further examine the potential role of Type D personality on out comes in allogeneic HSCT recipients. Type D personality may be a valuable indicator of patients at risk of significant psychosocial distress and negative health outcomes. In spite of the limitations discussed, the current study is the first study, to our k nowledge, to examine Type D personality in allogeneic HSCT recipients. Although these early findings are tentatively offered, future research incorporating suggested methodological improvements may offer firmer conclusions and provide a foundation for exam ining the effects of psychosocial interventions targeting inhibition and negative affect in HSCT recipients.

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36 LIST OF REFERENCES Andrykowski, M.A., Brady, M .J., & Henslee Downey, P.J. (1994). Psychosocial factors predictive of survival after allogeneic b one marrow transplantation for leukemia. Psychosomatic Medicine, 56(5), 432 439 Antoni, M. H., Lutgendorf, S. K., Cole, S. W., Dhabhar, F. S., Sephton, S. E., McDonald, P. G., and M. Stefanek, & Sood, A. K. (2006). The influence of bio behavioural factors on tumour biology : Pathways and mechanisms. Nature Reviews Cancer 6 240 248. Bishop M M W elsh, H., Coons, M., & Wingard, J.R. (2001). Blood and marrow transplantation. In J R Rodrigue (Ed.), Biopsychosocial perspectives on transplantation (pp. 19 37 ). Gainesville, FL: Kluwer Academic/Plenum Publishers. Canada A L F awzy, N. W. & Fawzy F I. (2005). Personality and disease outcome in malignant melanoma Journal of Psychosomatic Research 58 19 27. Center for Disease Control and Prevention (2010). C ytomegalovirus (CMV). Retrieved on January 9, 2010 from www.cdc.gov/cmv. Denollet, J. (1998). Personality and risk of cancer in men with coronary heart disease. Psychological Medicine 28 991 995. Denollet, J (1999). Type D personality : A potential risk factor refined. Journal of Psychosomatic Research 49 255 266. Denollet J C onraads, V. M. Brutsaert D L de Clerck L S Stevens W J & Vrints C J. (2003). Cytokines and immune activation in systolic heart failure the role of type d personality. Brain, Behavior, and Immunity 17 304 309. Denollet, J (2005). DS14 : Standard assessment of negative affectivity, social inhibition, and type d personality. Psychosom atic Med icine, 67 89 97. Denollet J V rints, C .J ., & Conraads V M. (2008). Comparin g type d personality and failure. Brain, Behavior, and Immunity 22 736 743. Essa, S., Pacsa, A., Raghupathy, R., Said, T., Nampoory, M.R.N., Johny, K.V., et al. (2009). Low levels of th1 type cytokines and increased levels of th2 type cytokines in kidney transplant recipients with active cytomegalovirus infection. Transplantation Proceedings, 41, 1643 1647. Ferguson, E., Williams, L., O'Conner R C Howard S Hughes B M Johnston D W. et al. (2009). A taxometric analysis of type d personality. Psychosomatic Medicine, 71(9), 981 986.

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38 Millon T ., Antoni, M., Millon C Meagher S & Grossman S. (2001). Test manual for the Millon Behavioral Medicine Diagnostic (MBMD). Minneapolis, MN: National Computer Services. Mols F Holterhues C., Nijsten T & van de Poll Franse L V ( in press ). Personality is associated with health status and impact of cancer among melanoma survivors. Eur opean J ournal of Cancer Molloy G J P erkins P orras, L., Strike P C & Steptoe A (2008). Type d personality and cortisol in survivors of acute coronary syndrome. Psychosomatic Medicine 70 (8) 863 868. National Cancer Institut e (2009) Bone marrow transplantation and peripheral blood stem cell transplantation. Retrieved October 11, 2009 from www.cancer.gov. Leary A. (1990). Stress, e mo tion and human immune function, Psychological Bulletin 108 (3) 363 382 Osarogiagbon R U D efor, T. E. Weisdorf M A Erice A & Weisdorf D J. (2000). CMV antigenemia following bone marrow transplantation: risk factors and outcomes. Biology of Blood and Marrow Transplant 6(3), 280 288. Padron E S chold, J., Dallas J Levine J & Reddy V A. (2008). Association of early post transplant interferon leve ls and CMV infection after HSCT [Abstract]. American Society of Clinical Oncology 26( 15S ), Abstract No. 7095 Pedersen S S H errmann L ingen, C., de Jonge, P., & Scherer, M. (2010 ). Type d personality is a predictor of poor emotional quality of life in primary care heart failure patients independent of depressive symptoms and New York Heart Association functional class. Journal of Behavioral Medicine 33(1), 72 80. Pennebaker, J.W., Colder, M. and Sharp, L.K. (1990). Accelerating the coping process. Journal of Personality and Social Psychology, 58(3), 528 537. Rawlinson W & S cott, G. (2003). Cytomegalovirus: A common virus causing serious disease. Australian Family Physician 32 (10) 789 793. Reddy V W iner, A. G. Eksioglu E Meier Kriesche H U Schold J D & Wingard J R. (2005). Interleukin 12 is associated with reduced relapse without increased incidence of graft versus host disease after allogeneic hematopoietic stem cell transplantation. Biology of Blood and Marrow Transplant 11(12), 1014 1021. Reddy V ., Meier Kriesche H., Greene S Schold J D & Wingard J R (2005). Increased levels of tumor necrosis factor alpha are associated with an increased risk of cytomegal ovirus infection after allogeneic hematopoietic stem cell transplantation. Biology of Blood and Marrow Transplant 11 (9) 698 705.

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39 Reinke P P rosch, S., Kern F & Volk H D. (1999). Mechanisms of human cytomegalovirus (HCMV) (re)activation and its impa ct on organ transplant patients. Transplant and Infectious Diseases 1(3), 157 164 Sanderman R & R anchor, A. (1997). The predictor status of personality variables etiological significance and their role in the course of disease. European Journal of Pe rsonality 11 359 382. Segerstrom, S C (2003). Individual differences, immunity and cancer lessons from personality psychology. Brain, Behavior, and Immunity 17 S92 S97. Thomas, S. P. (1986). A descriptive profile of t ype b personality. Image: Journal ofNursing Scholarship 18, 4 7. Abstract obtained from PubMed. Torres H A Kontoyiannis D., Aguilera E A Younes A Luna M A Tarrand J J et al (2006). Cytomegalovirus infection in patients with lymphoma an important cause of morbidity and m ortality. Clinical Lymphoma and Myeloma 6 (5) 393 398 Van Rood, Y.R., Bogaards, M., Goulmy, E., and van Houwelingen, H.C. (1993). The effects of stress and relaxation on the in vitro immune response in man: a meta analytic study. Journal of Behavioral Me dicine, 16(2), 163 181.

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40 BIOGRAPHICAL SKETCH Seema M Patidar attended the University of North Carolina where she e arned a Bachelor of Science in psychology, with a minor in c hemistry in 2006. After graduating, Seema worked at Duke University Medical Cente r on a study examining the prognostic benefits of exercise and anti depressant therapy in patients with heart disease. Health Psychology PhD program. She began her graduate education in 2008 and was research lab conducting research in psycho