Regulation of mRNA expression encoding chaperone and co-chaperone proteins of the glucocorticoid receptor in peripheral blood: association with depressive symptoms during pregnancy.

BACKGROUND: Major depressive disorder during pregnancy associates with potentially detrimental consequences for mother and child. The current study examined peripheral blood gene expression as a potential biomarker for prenatal depressive symptoms. METHOD: Maternal RNA from whole blood, plasma and the Beck Depression Inventory were collected longitudinally from preconception through the third trimester of pregnancy in 106 women with a lifetime history of mood or anxiety disorders. The expression of 16 genes in whole blood involved in glucorticoid receptor (GR) signaling was assessed using real-time polymerase chain reaction. In parallel, plasma concentrations of progesterone, estradiol and cortisol were measured. Finally, we assessed ex vivo GR sensitivity in peripheral blood cells from a subset of 29 women. RESULTS: mRNA expression of a number of GR-complex regulating genes was up-regulated over pregnancy. Women with depressive symptoms showed significantly smaller increases in mRNA expression of four of these genes - FKBP5, BAG1, NCOA1 and PPID. Ex vivo stimulation assays showed that GR sensitivity diminished with progression of pregnancy and increasing maternal depressive symptoms. Plasma concentrations of gonadal steroids and cortisol did not differ over pregnancy between women with and without clinically relevant depressive symptoms. CONCLUSIONS: The presence of prenatal depressive symptoms appears to be associated with altered regulation of GR sensitivity. Peripheral expression of GR co-chaperone genes may serve as a biomarker for risk of developing depressive symptoms during pregnancy. The presence of such biomarkers, if confirmed, could be utilized in treatment planning for women with a psychiatric history.

Altered prestarvation response in a nystatin resistant Dictyostelium discoideum mutant.

Wild-type Dictyostelium amoebae secrete an autocrine, prestarvation factor (PSF) that allows them to measure the amount of food bacteria compared to their cell density. When the ratio of PSF to bacteria reaches a threshold, the cells are signaled to prepare for eventual starvation. This prestarvation response (PSR) usually starts three to four generations before the end of exponential growth, leading to the accumulation of several aggregation specific genes during growth. We characterize a nystatin-resistant mutant, HK19, that expresses the PSR genes three generations earlier than wild type but has an otherwise wild-type PSR. Although HK19 has a full PSR during growth, HK19 continues to grow at the wild-type rate and reaches normal cell densities. Because HK19 temporally separates the PSR from starvation, it became possible to test whether starvation is required for development. Since HK19 growing at low density can be induced to clump with either cAMP or folate, it appears that the PSR and an external signal are sufficient for entry into development. These data suggest that the PSR is a complex genetic pathway that induces genes involved in the exit from growth and the entry into development.

Children's memories for painful cancer treatment procedures: implications for distress.

Children (ages 3 to 18, N = 55) diagnosed with leukemia were tested for their memories of lumbar punctures (LPs), a repeated and painful part of the cancer treatment protocol. Memory for both event details and the child's emotional responses was assessed one week after the LP. Children of all ages displayed considerable accuracy for event details, and accuracy increased with age. Overall recall accuracy for event details and emotional responses was similar. Recall among children given oral Versed was similar to that among children not given Versed. Finally, higher distress predicted greater exaggerations in negative memory 1 week later (although controlling for age weakened this relationship); moreover, greater exaggerations in negative memory predicted higher distress at a subsequent LP. These results indicate that children's memories play an important role in their experience of distress during repeated stressful events.

Mediation of cell-substratum adhesion by RasG in Dictyostelium.

Previous studies on the functions of the RasG gene in the cellular slime mold, Dictyostelium discoideum, have revealed that it is required for normal motility and cytokinesis. To further understand how the RasG gene regulates various cellular processes, we transformed an activated form of RasG, that is, RasG (G12T), a mutation from glycine to threonine at amino acid position 12 into wild type KAX-3 cells. This produced moderate but constitutive RasG(G12T) protein expression, which causes cells to become significantly more adherent to the substratum than are wild type cells. The RasG(G12T) transformants also grow slowly on bacterial plates, and engulf fewer bacteria on filter surfaces, indicating a defect in phagocytosis when cells are adhered. The expression of the activated RasG also dramatically reduces the number of filopodia on the cell surface. Tyrosine phosphorylation on a 43 kDa protein (most likely actin) of the RasG (G12T) transformants is highly elevated. Taken together, our observations suggest that RasG is crucial for Dictyostelium cell-substratum adhesion during growth and that RasG may play a role in adhesion-mediated phagocytosis. Our results also suggest that RasG is important in filopodial formation and that RasG is involved in the signal pathway that is regulated by tyrosine phosphorylation.

Pain-sensitive temperament: does it predict procedural distress and response to psychological treatment among children with cancer?

OBJECTIVE: To evaluate the relationship between pain sensitivity and children's distress during lumbar punctures (LPs), and whether pain sensitivity functions as a moderator of children's responses to a psychological intervention aimed at reducing LP distress. METHOD: Fifty-five children with acute lymphoblastic leukemia (ages 3 to 18) and their parents completed a questionnaire measure of pain sensitivity. Self-report, physiological, and observed measures of distress were collected during the study baseline LP. Children were then randomized into a psychological intervention or an attention control group. Postintervention and follow-up LPs were observed. RESULTS: Higher levels of pain sensitivity were associated with greater anxiety and pain, both prior to and during the LP. Preliminary analyses indicated that pain sensitivity moderated the effects of intervention on distress. Children who were more pain-sensitive and who received no intervention showed greater increases in LP distress over time. In contrast, children who were more pain-sensitive and who received intervention showed greater decreases in LP distress over time. CONCLUSIONS: A measurement of pain sensitivity may be useful in pediatric oncology settings for effectively targeting pain-vulnerable children for psychological intervention. Preliminary analyses indicate that an empirically-supported intervention for procedural distress is efficacious for those children who are most pain-sensitive.

The Pediatric Cancer Quality of Life Inventory-32 (PCQL-32). II. Feasibility and range of measurement.

The Pediatric Cancer Quality of Life Inventory-32 (PCQL-32) has been developed to be a standardized assessment instrument to assess systematically pediatric cancer patient's health-related quality of life (HRQOL) outcomes. Multidimensional serial measurement of pediatric cancer patients' HRQOL in Phase III randomized controlled clinical trials is increasingly being recognized as an essential component in evaluating the comprehensive health outcomes of modern antineoplastic treatment protocols. The 32-item PCQL-32 short form was empirically derived from the PCQL long form (84-87 items), which was administered to 291 pediatric cancer patients and their parents during various stages of treatment. The feasibility (percentage of missing values per item) and range of measurement [percentage of minimum (floor effect) and maximum (ceiling effect) possible scores] was calculated for the five PCQL-32 scales and the total scale score. Feasibility for the PCQL-32 was very good, with less than .01% missing values. Range of measurement was full, with no ceiling effects (higher symptoms/problems) and low to moderate floor effects (lower symptoms/problems). The PCQL-32 demonstrated very good feasibility and range of measurement. In its short form, the PCQL-32 is practical for Phase III clinical trials. Future studies will test the utility of the PCQL-32 as a brief serial measure for monitoring the HRQOL outcomes for children and adolescents with cancer.

Alteration of memory in the reduction of children's distress during repeated aversive medical procedures.

The present study sought to reduce children's distress during aversive medical procedures using a brief, cost-effective intervention aimed at reframing memory. Fifty children diagnosed with leukemia (25 treatment, 25 attention control, aged 3-18) were observed as they underwent 3 consecutive lumbar punctures (LPs; baseline, postintervention, and follow-up). Self-report, physiological, and observable distress measures were collected before and after each LP. At posttreatment, children in the intervention group showed reductions in anticipatory physiological and self-report ratings relative to the control group. At follow-up, these effects generalized to reductions in procedural distress. These results suggest that (a) a simple memory-based intervention is efficacious at reducing children's distress and (b) benefits from this intervention are maintained over 1 week even without continued intervention.

The Pediatric Cancer Quality of Life Inventory: a modular approach to measuring health-related quality of life in children with cancer.

Measurement of pediatric cancer patients' health-related quality of life (HRQL) in phase III randomized, controlled clinical trials is being recognized increasingly as an essential component in evaluating the comprehensive health outcomes of modern anti-neoplastic treatment protocols. Use of a brief core measure of HRQL plus disease-specific symptom modules is a way to assess specific HRQL outcomes with a minimum of subject burden. Demonstrating a measure's feasibility, reliability and validity also represents children's ability to provide reliable and valid responses to HRQL questions. The Pediatric Cancer Quality of Life Inventory (PCQL) Modular Approach consists of a 15-item core measure of HRQL and 2 specific symptom modules: pain and nausea. To validate a patient-report form and a parent-report form, the PCQL was administered to 291 pediatric cancer patients and to their parents. Feasibility and range of measurement, as well as patient-parent concordance, were assessed. Internal consistency reliability was assessed via Cronbach's alpha. Validity was determined by the known-groups approach and by correlating PCQL scores with days missed from school. Patients had minimal missing data, and the range of measurement for the items was good. Patient-parent concordance was large but not perfect. For both patient and parent forms, internal consistency reliability of the PCQL core scale (0.83 and 0. 86, respectively) was strong. The internal consistency reliabilities of the 2 symptom modules for both patient and parent forms were in the acceptable range for group comparisons. Regarding clinical validity, the core scale and the 2 symptom modules distinguished between patients on and off treatment for both patient and parent reports. Further, both patient and parent reports correlated with days of missed school in the past 6 and 12 months. The PCQL Modular Approach has demonstrated acceptable internal consistency reliability and clinical validity for both patient-report and parent-report forms. By implication, children are capable of providing reliable and valid responses to these HRQL questions.

The Pediatric Cancer Quality of Life Inventory (PCQL). I. Instrument development, descriptive statistics, and cross-informant variance.

Intensive antineoplastic treatment protocols have been developed and implemented in controlled clinical trials with the goal of improving the survival of pediatric cancer patients. Multidimensional health outcome evaluation of this cohort of pediatric cancer patients being treated with these modern regimens is essential in order to enhance health-related quality of life. The Pediatric Cancer Quality of Life Inventory (PCQL) was developed to be a standardized assessment instrument to assess systematically pediatric cancer patient's health-related quality of life outcomes. The PCQL was administered to 291 pediatric cancer patients and their parents at various stages of treatment. The aim of the present study was to present the development, descriptive statistics, and cross-informant variance for the PCQL items. Large variability in symptoms and health-related problems were found as expected given the wide heterogeneity in the patient population sampled. Patient/parent concordance on individual items averaged in the medium effect size range. The findings underscore the importance of measuring both patient report and parent report of patient symptoms and problems in pediatric cancer health-related quality of life assessment.

The pediatric cancer quality of life inventory-32 (PCQL-32): I. Reliability and validity.

BACKGROUND: Multidimensional measurement of pediatric cancer patients' health-related quality of life (HRQOL) in Phase III randomized controlled clinical trials is being recognized increasingly as an essential component in evaluating the comprehensive health outcomes of modern antineoplastic treatment protocols. The Pediatric Cancer Quality of Life Inventory-32 (PCQL-32) is a standardized patient self-report and parent proxy-report assessment instrument designed to assess systematically pediatric cancer patients' HRQOL outcomes. METHODS: To validate a patient-report form and a parent-report form, the PCQL-32 was administered to 291 pediatric cancer patients and to their parents. Both forms yield a total score and five a priori multidimensional scales. Clinical validity was determined by the known-groups approach by comparing patients classified as either on or off treatment. To determine construct validity, a battery of standardized psychosocial measures was administered and a multitrait-multimethod matrix was constructed. RESULTS: For both patient and parent forms, internal consistency reliability of the PCQL-32 total scale was high (0.91 and 0.92, respectively). The internal consistency reliabilities of the five component scales for both patient and parent forms were in the acceptable range for group comparisons. With regard to clinical validity, the PCQL-32 total scale and the disease/treatment and physical functioning scales of the PCQL-32 distinguished between patients on and off treatment for both patient- and parent-report. The results of the multitrait-multimethod matrix approach were consistent with hypotheses and lent evidence for the construct validity of the patient and parent forms of the PCQL-32 total scale and the psychological functioning, social functioning, cognitive functioning, physical functioning, and disease/treatment scales. CONCLUSIONS: The PCQL-32 has demonstrated acceptable internal consistency reliability, clinical validity, and construct validity for both patient-report and parent-report forms. Further field testing of the PCQL-32 will determine its practicality and utility in multisite pediatric cancer randomized controlled clinical trials.

Family functioning predictors of adjustment in children with newly diagnosed cancer: a prospective analysis.

Theoretically-driven investigations on the potentially modifiable predictors of individual differences among newly-diagnosed pediatric cancer patients may facilitate the identification of children at risk for adjustment problems. Within a risk and resistance conceptual model, family functioning was investigated concurrently and prospectively as a predictor of adjustment in newly-diagnosed pediatric cancer patients at Time 1 (within 1 month after diagnosis), Time 2 (6 months postdiagnosis), and Time 3 (9 months postdiagnosis). The family relationship dimensions of cohesion and expressiveness most consistently predicted the psychological and social adjustment of children with newly-diagnosed cancer over a 9-month period after initial diagnosis. These findings are discussed in terms of the treatment implications for enhancing child adjustment to newly-diagnosed cancer and biomedical treatment.

Perceived physical appearance and adjustment of children with newly diagnosed cancer: a path analytic model.

More intensive medical treatment protocols have been initiated with the goal of improving survival of pediatric cancer patients. Evaluation of the adjustment of this cohort of children with newly diagnosed cancer being treated with these modern regimens is essential in order to enhance quality of life. Children with cancer who experience disease and treatment-related changes in physical appearance are hypothesized to be at greater risk for psychological and social adjustment problems given society's attitudes toward visible physical differences. Within a risk and resistance theoretical framework, perceived physical appearance was investigated as a predictor of depressive symptoms, social anxiety, and general self-esteem in newly diagnosed pediatric cancer patients. In support of the a priori conceptual model, path analysis findings indicate that perceived physical appearance has direct and indirect effects on depressive symptoms and social anxiety with the indirect effects mediated by general self-esteem. Exploratory analysis suggests that the effect of perceived physical appearance on general self-esteem may be attenuated by modifiable competence/adequacy domains which have implications for the development of treatment interventions for children with newly diagnosed cancer.

Perceived social support and adjustment of children with newly diagnosed cancer.

The negative impact on psychologic adjustment from the stress of living with newly diagnosed cancer is hypothesized to be affected by perceived social support. Thirty children with newly diagnosed cancer completed standardized assessment instruments measuring depressive symptoms, state anxiety, trait anxiety, social anxiety, general self-esteem, and perceived social support from classmates, parents, teachers, and friends. Their parents completed a standardized assessment instrument measuring internalizing and externalizing behavior problems. Perceived classmate, parent, and teacher social support were variously correlated with the psychologic adjustment parameters in the hypothesized direction of greater support predicting lower psychologic distress and higher self-esteem. Hierarchical multiple regression analyses identified perceived classmate social support as the most consistent predictor of adaptation, providing further evidence of the essential function of the social environment of the school setting in affecting the adjustment of children with newly diagnosed cancer.

The impact of social skills training on the adjustment of children with newly diagnosed cancer.

Randomized 64 children ages 5 to 13 years with newly diagnosed cancer to either a Social Skills Training experimental treatment group or a School Reintegration standard treatment group. Children who received explicit training in social skills reported higher perceived classmate and teacher social support at the 9-month follow-up in comparison to pretreatment levels, while parents reported a decrease in internalizing and externalizing behavior problems and an increase in school competence. Methodological improvements for Phase III clinical trials are addressed.

Social support and social cognitive problem-solving in children with newly diagnosed cancer.

Children newly diagnosed with cancer have been documented to be at increased risk for difficulties in their return to school and ongoing positive social experiences. This article reviews the critical role of social support in helping children adjust to their illness and treatment. Social skills training for newly diagnosed children is presented as an important intervention strategy for increasing positive social interactions and overall psychosocial adjustment. A randomized, clinical research trial currently in progress that will evaluate the impact of social skills training on newly diagnosed children 5-13 years of age is delineated. The potentially positive impact of social skills training on the prevention of emotional problems and increased biologic survival are discussed.

Teacher, parent, and child evaluative ratings of a school reintegration intervention for children with newly diagnosed cancer.

The disruption of school participation and accompanying social experiences because of cancer and its treatment has been related to major problems in adaptation to the disease. For the child with cancer, continuation of his/her social and academic activities provides an important opportunity to normalize as much as possible a very difficult experience. The present study reports on the children's, parents', and teachers' subjective evaluations of the benefits of a comprehensive school reintegration intervention. Forty-nine children, newly diagnosed with cancer, received comprehensive school reintegration consisting of supportive counseling, educational presentations, systematic liaison between the hospital and the school, and periodic follow-ups. Children parents, and teachers were asked to rate their perceptions of the utility and value of the intervention approach. Overall subjective evaluations were very positive, providing support for the social validity of the school reintegration approach for children with newly diagnosed cancer.

Memory for spatial location in retarded and nonretarded persons.

Item memory and memory for spatial location were examined in college students, mildly retarded persons and moderately retarded persons. They performed under semantic or nonsemantic encoding instructions to remember pictures presented in a large book. Recall and relocation (unexpected) tests followed immediately after studying the pictures and, again, 24 h later. Mildly retarded persons were deficient in memory for items (effortful processing), but not in memory for location (automatic processing). Moderately retarded persons were deficient in both types of memory. Additionally, there were IQ-related differences in the long-term memory of location information, as well as item information. Location memory, as opposed to item memory, was shown to be (1) sensitive to encoding instruction, (2) insensitive to differences in intelligence, and (3) more sensitive to long-term forgetfulness.