In their own words: using the common sense model to analyze patient descriptions of cancer-related fatigue.

PURPOSE/OBJECTIVES: To describe cancer-related fatigue (CRF) from the perspective of individuals experiencing it and examine the fit of their descriptions with the concepts from the Common Sense Model (CSM). DESIGN: Exploratory, qualitative design, SAMPLE: A convenience sample of eight patients with cancer known to be experiencing fatigue from the outpatient clinic. METHODS: Content analysis of data obtained from focus groups. FINDINGS: All statements describing CRF could be classified using the major constructs of the CSM: representation, coping, and appraisal. The majority of statements were classified as representations of fatigue (67%), with smaller proportions classified as coping (26%) and appraisal (7%). CONCLUSIONS: This study provides evidence to support the validity of the CSM constructs as an organizing framework in the conduct of research. IMPLICATIONS FOR NURSING PRACTICE: This study demonstrates the usefulness of the model In clinical assessment of patient representations of CRF as well as coping strategies for managing it The model is particularly useful in targeting knowledge deficits and inaccuracies.

Psychometric testing of fatigue instruments for use with cancer patients.

BACKGROUND: Cancer treatment-related fatigue (CRF) is a common side effect of cancer treatment. A problem identified in most reviews of CRF is lack of sound approaches to measurement that are congruent with the conceptualization of CRF as a self-perceived state. The diversity of instruments available to measure fatigue and the lack of comprehensive testing of several promising instruments with cancer patients undergoing treatment provided the rationale for this study. The purpose of this article is to report the results of psychometric testing of several fatigue instruments in patients undergoing cancer treatment. OBJECTIVES: The aims of this study were to determine the reliability, validity, and responsiveness of each instrument and to determine the ability of each instrument to capture CRF. METHODS: Existing fatigue instruments with published psychometric information that indicated suitability for further testing were selected and included the Profile of Mood States Short Form fatigue subscale (F_POMS-sf), Multidimensional Assessment of Fatigue (MAF), Lee Fatigue Scale (LFS), and the Multidimensional Fatigue Inventory (MFI). Data were collected at a university-based clinical cancer center and a freestanding comprehensive cancer center. Subjects completed all study instruments, which were presented in random order, at a time when CRF was expected to be high and again when it was expected to be low. A subset of subjects completed the instruments within 48 hours of one of the data collection points when CRF was expected to be relatively unchanged to provide stability data. RESULTS: Reliability estimates using Cronbach's alpha indicated that all instruments examined had good internal consistency. Test-retest correlations showed good stability for total scores on all the instruments, but some subscales of the LFS and MFI had marginal stability. Factor analysis of all instruments indicated that only the LFS and the F_POMS-sf fully supported their construct validity. All of the instruments showed responsiveness to changes in CRF related to treatment. CONCLUSIONS: The results of the study provide researchers and clinicians with detailed comparisons of the performance of established fatigue measures in cancer patients undergoing treatment to use when selecting measures of CRF.

Planning and conducting a multi-institutional project on fatigue.

PURPOSE/OBJECTIVES: To describe the process used in proposal development and study implementation for a complex multisite project on cancer treatment-related fatigue (CRF), identify strategies used to manage the project, and provide recommendations for teams planning multisite research. DATA SOURCES: Information derived from project team meeting records, correspondence, proposals, and personal recollection. DATA SYNTHESIS: The project was built on preexisting relationships among the three site investigators who then built a team including faculty, research coordinators, staff nurses, and students. Study sites had a range of organizational models, and the proposal was designed to capitalize on the organizational and resource strengths of each setting. Three team members drawn from outside oncology nursing provided expertise in measurement and experience with fatigue in other populations. Planning meetings were critical to the success of the project. Conference calls, fax technology, and electronic mail were used for communication. Flexibility was important in managing crises and shifting responsibility for specific components of the work. The team documented and evaluated the process used for multisite research, completed a major instrumentation study, and developed a cognitive-behavioral intervention for CRF. CONCLUSIONS: Accomplishments during the one-year planning grant exceeded initial expectations. The process of conducting multisite research is complex, especially when the starting point is a planning grant with specific research protocols to be developed and implemented over one year. Explicit planning for decision-making processes to be used throughout the project, acknowledging the differences among the study settings and planning the protocols to capitalize upon those differences, and recruiting a strong research team that included a member with planning grant and team-building expertise were essential elements for success. IMPLICATIONS FOR NURSING PRACTICE: Specific recommendations for others planning multisite research are related to team-building, team membership, communication, behavioral norms, role flexibility, resources, feedback, problem management, and shared recognition.

CD8+ cells are not necessary for allograft rejection or the induction of apoptosis in an experimental model of small intestinal transplantation.

Allospecific CTL can function as cellular effectors of solid organ graft rejection; however, the specific mechanisms of cell damage remain undetermined. In this study we examined the role of CD8+ T cells in apoptosis and rejection of small intestinal allografts. ACI rat intestinal grafts transplanted into Lewis rat recipients showed apoptosis of epithelial crypt cells on day 3 posttransplant as determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling staining. By day 7 numerous apoptotic crypt cells were detected in allografts, but were rarely observed in FK506-treated allograft recipients, isografts, or native intestine of allograft recipients. To further investigate the mechanism of rejection, recipient rats were depleted of CD8+ cells by treatment with OX-8 mAbs the day before and the day after transplantation of rat small intestinal allografts. Depletion of CD8+ cells from allograft recipients did not alter the tempo or the histologic features of rejection compared with those in the control (IgG-treated) group. Moreover, there was no difference in the number of apoptotic crypt epithelial cells in the grafts of control and CD8-depleted rats. Reverse transcriptase-PCR analyses determined there were similar levels of transcripts for Fas, Fas ligand, perforin, and granzyme B in control and CD8-depleted allograft recipients. By Western blot it was determined that the levels of Fas ligand protein were increased in the CD8-depleted group compared with those in control and FK506-treated allograft recipients. These data suggest that CD8 cells are not required for tissue injury or apoptotic cell death in small intestine allograft rejection.

Induction of tolerance to human gamma-globulin in FcR gamma- and Fc gammaRII-deficient mice.

FcR gamma-deficient mice were used to examine the role of Fc gamma receptors in the induction of peripheral tolerance to human gamma-globulin (HGG). FcR gamma-deficient mice injected with HGG in adjuvant demonstrated a CD4+ T cell response to in vitro challenge with HGG, as assayed by proliferation, cytokine secretion, and Ag-specific help for B cell Ab production. In vitro kinetics of Ag-specific proliferation were similar in both conventional and knockout mice. Peripheral tolerance could be established in these mice with a single dose of deaggregated protein, despite the lack of functional Fc gammaRI, the high affinity receptor for monomeric IgG. Establishment of unresponsiveness was observed at both the T and B cell levels. T cell tolerance was manifested in the reduction of T cell helper function and Ag-induced release of Th1- and Th2-like cytokines, as well as decreased proliferation to Ag-specific stimulation. B cell tolerance was demonstrated in knockout and normal mice by failure to detect HGG-specific Ab production using an immunization protocol for Ab production that bypasses the need for Ag-specific T cells. These results demonstrate that induction of tolerance in CD4+ cells to HGG does not require transduction of a signal through Fc gammaRI. Furthermore, the ability to induce tolerance to HGG in B cells in Fc gammaRII-deficient mice suggests that down-regulation of Ag-specific B cells through Fc gammaRII is not the mechanism by which B cell tolerance is induced. However, Fc gammaRII plays a role in regulating the immune response since the Ab response to immunogenic HGG in Fc gammaRII-deficient mice is markedly enhanced.

Quality of life and nutritional support in patients with cancer.

Nutritional support is often initiated in patients with cancer who are unable to meet their nutritional needs by the oral route. Much has been written about the effect of nutritional support on physiological outcomes in patients with cancer. However, less is known about the relationship between improvement of nutritional status and quality of life. Trends in the treatment of cancer highlight the need for an examination of home nutrition support and quality of life. The purpose of this article is to describe the state of knowledge about the relationship of home enteral and parenteral nutrition support and quality of life. Research exploring the dimensions of quality of life (physical functioning, psychological status, interpersonal relationships and social functioning, financial concerns, and symptoms, and complications of nutritional support) is presented. Implications for clinical practice and research are identified. The trend for increased numbers of patients on home nutrition support emphasizes the need to understand the patient's and family's experience in managing this treatment in the home.

Thymic epithelial cell abnormalities in (NZB x H-2u)F1 mice.

Thymic maturation processes including MHC restriction and self-recognition require intimate association of thymocytes and stromal cells. Compared to the thymic architecture of various "normal" control strains of mice, defects in the thymic microenvironment have been demonstrated in New Zealand black (NZB) mice. Moreover, it is well known that NZB(H-dd) mice, when crossed with NZW(H-2u) mice, (NZB x NZW)F1, display a unique spectrum of autoimmune disease manifestations, including murine SLE. Using an extensive panel of monoclonal antibodies that define the thymic microenvironment, we examined two additional strains of (NZB x H-2u)F1 mice: (NZB x C57BL/10.PL)F1 and (NZB x PL/J)F1 mice to investigate the contributions of the H-2 and non-H-2 loci to the thymic abnormalities previously documented to occur in murine lupus. NZB, NZW, and (NZB x NZW)F1 mice were studied concurrently as were two additional control strains C57BL/6 and C57BL/10Sn. NZW mice had a normal thymic architecture as did the other H-2u mice and the control strains. In contrast, (NZB x NZW)F1 mice had a significantly altered thymic microenvironment; mild thymic abnormalities were also found in (NZB x PL/J)F1 but not in (NZB x C57BL/10.PL)F1. As expected, (NZB x NZW)F1 mice developed elevated titers of autoantibodies to DNA, proteinuria, and decreased life span. Interestingly, only (NZB x PL/J)F1 mice had increased levels of IgM antibodies to dsDNA, but did not manifest IgG anti-DNA or reduced survival. Defects in thymic stromal cells are associated directly to autoimmunity and their origin appears to be determined by non-H-2 loci.

HIV-1 expression during early mammalian development.

OBJECTIVE: Our long-term objective is to determine the consequences of HIV-1 expression in the mammalian fetus using the mouse as a model system. This study describes HIV gene expression in micro-injected and electroporated embryos during the pre-implantation period. DESIGN: Procedures were adopted to create a non-infectious HIV system to assay HIV long terminal repeat (LTR) activation in a non-human mammal. METHODS: Two constructs (RSV promoter-HIV tat gene; HIV LTR-lac Z gene) were co-micro-injected (10 micrograms/ml each) into pronuclei of fertilized eggs or one nucleus of the two-cell stage and expression assessed after 2-5 days. The techniques of electroporation and micro-injection were compared for their ability to deliver the constructs expressed subsequently. RESULTS: We found that HIV-1 expression, as monitored by beta-galactosidase production, can occur as early as the eight-cell to blastocyst stage. The intensity of HIV expression varied from high to low; the proportion of the embryo expressing HIV varied from half to only two cells. The material was too limited to allow a determination of integration. CONCLUSIONS: The expression rate of the HIV-LTR was low, averaging slightly over 1%. The data demonstrate that the HIV-LTR can be activated in early mammalian development, even before implantation. This information is valuable to those studying HIV-transgenic mice, to those interested in factors governing HIV expression, and to those concerned about pathologies accompanying developmental expression of HIV.

Characterization of two genes for the human Na,K-ATPase beta subunit.

A total of 29 human genomic DNA clones that hybridize with cDNAs for the sheep and rat Na,K-ATPase beta subunits have been isolated, classified by restriction endonuclease mapping and Southern blot hybridization analysis, and sequenced. One class of clones, designated ATP1BL1, represents a processed pseudogene for the beta subunit. The second class, designated ATP1B, includes 15 overlapping genomic clones and represents a functional gene for the human Na,K-ATPase beta subunit. ATP1B spans about 26.7 kb of genomic DNA and includes 24 kb of intron sequence. The complete mRNA transcript for the human beta subunit is encoded by six exons, ranging in size from 81 to 1427 bp. Primer extension and S1 nuclease protection experiments with human kidney RNA indicate the presence of two major transcription initiation sites at -510 and -201 to -191, with minor initiation sites at -268, -182 to -174, and -142. The distal initiation site at -510 is preceded by consensus sequences for CAAT and TATA boxes. The DNA sequence preceding the proximal heterogeneous initiation sites contains a CAAT box, but no TATA box. Two of the 12 GC boxes (GGCGGG and CCCGCC) located in the 5' region of ATP1B are located between this CAAT box and the proximal clusters of transcription initiation sites.

Effect of calcium channel modulators on isolated endothelial cells.

Indirect evidence, using organic calcium channel modulators suggests that calcium channels exist in endothelial cells. Using freshly prepared and cultured bovine aortic endothelial cells, we have studied the effect of calcium channel modulators on Fura-2 fluorescence and have examined the binding of the dihydropyridine, (+)[3H]PN200-110. In both isolated primary and cultured cells, external calcium (0.5-2 mM) and bradykinin (10(-8) M) increased the intracellular calcium concentration. In cultured cells, the increase in calcium was not significantly attenuated by preincubation with nitrendipine (10(-8) M) or d-cis-diltiazem (10(-6) M). The calcium agonists (-)Bay k8644 and (+)202-791 had no effect on intracellular calcium concentration, but other agonists including ATP (10(-4) M) and thrombin (1.5 micrograms/ml) significantly increased the calcium concentration. Competition binding studies with (+)[3H]PN200-110 indicated specific binding of this ligand with a KD of 57 nM and a Bmax of 2.1 pmol/10(6) cells. While these data do not provide convincing evidence for the existence of calcium channels in cultured or fresh bovine aortic endothelial cells, explanations may yet reconcile our observations with the presence of calcium channels in these cells.

Sodium-calcium exchange exists across the cell membrane of intact vascular smooth muscle cells.

Ouabain stimulated Ca2+ uptake in rat aortic smooth muscle cells in culture. The maximum uptake of Ca2+ was observed at about 200 mumol/l ouabain. Na+K+-ATPase activity of these cells was also maximally inhibited at about 200 mumol/l ouabain. The ouabain-stimulated Ca2+ uptake was not inhibited by the calcium antagonist diltiazem. The cells treated with ouabain also showed increased steady-state cytosolic Ca2+ concentration as measured by the fluorescent dye indicator Fura 2/AM. The ouabain stimulated Ca2+ uptake and increased cytosolic Ca2+ is explained as follows: ouabain inhibits Na+K+-ATPase with subsequent increase in cytosolic Na+, which is then exchanged with external Ca2+ through the Na+-Ca2+ exchange in intact vascular smooth muscle cells.

Myocardial Na, K-ATPase in one-kidney, one-clip hypertensive rats.

Myocardial ventricular Na, K-ATPase activity of normotensive rats was compared with that of healthy rats with chronic benign one-kidney, one-clip hypertension. The yield of protein (mg/g wet wt left plus right ventricles) in microsomal and sarcolemmal membrane fractions was the same for both normotensive and hypertensive rat ventricles. However, the yield of protein (mg/ventricle) was 26% greater in the hypertensive relative to the normotensive animals, consistent with the presence of hypertrophy, as also indicated by an increase in the ratio of ventricular to body weight and a shift in the isomyosin composition. Na, K-ATPase activity, sodium-dependent phosphorylation and ouabain binding were significantly (P less than 0.05) decreased (by 20%, 40%, and 45%, respectively) in the hypertensive rat ventricles when the data were expressed in units/g tissue wet weight. However, when expressed in units per ventricle, values in normotensive and hypertensive animals were similar. The molecular activity or turnover number of ventricular (and also renal) Na, K-ATPase activity was the same in both groups of animals. These results suggest that the decrease in myocardial specific Na, K-ATPase activity in the rat made hypertensive by removing one kidney and constricting the renal artery of the other kidney is related to the presence of cardiac hypertrophy.

Studies on the mechanism of action of 3, 4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-qu inolinone (OPC-8212), a new positive inotropic drug. Enzyme activities and Ca2+ transport processes of sarcolemma and intracellular organelles.

3,4-Dihydro-6-[4-(3,4- dimethoxybenzoyl )-piperazinyl]-2(1H)- quin olinone ( OPC -8212) is a new positive inotropic agent. In studies designed to elucidate information concerning its mechanism of action, its effect on Ca+ transport and related enzyme activities in sarcolemma, sarcoplasmic reticulum and mitochondria were studied. OPC -8212 was found to have little or no effect on these processes. The mechanism of action therefore is clearly different from other known positive inotropic drugs.

Decrease in Na+,K+-ATPase activity and [3H]ouabain binding sites in sarcolemma prepared from hearts of spontaneously hypertensive rats.

Na+,K+-ATPase activity, phosphorylation, and [3H]ouabain binding in sarcolemma isolated from spontaneously hypertensive rat (SHR) hearts were compared to the same parameters in sarcolemma from normotensive rat (WKY) hearts. Sarcolemma prepared from SHR heart contained significantly less ouabain-inhibitable ATPase activity than sarcolemma from WKY heart. No significant differences in sarcolemmal protein content or recovery were noted between the two groups. The numbers of phosphorylation sites and ouabain binding sites were lower for SHR hearts than for WKY hearts. The KD values for ouabain binding were the same (0.30 muM) in cardiac sarcolemma of SHR and WKY. The I50 values for inhibition by ouabain of Na+,K+-ATPase were also the same for both groups (SHR = 49 microM; WKY = 44 microM). These data suggest that the decrease of cardiac sarcolemmal Na+,K+-ATPase activity in SHR hearts is due to a decrease in the number of active sites.

[3H]nimodipine specific binding to cardiac myocytes and subcellular fractions.

[3H]Nimodipine binding was studied in isolated myocytes from rat heart and in partially purified sarcolemma, sarcoplasmic reticulum and mitochondrial fractions from dog heart. In isolated myocytes, the density of [3H]nimodipine specific sites (10(6) per cell) was close to density of [3H]QNB sites (0.8 x 10(6) per cell) and higher than that of [3H]DHA sites (0.2 x 10(6) per cell). During subcellular fractionation, [3H]nimodipine binding did not copurify with plasma membrane markers. The highest densities were found in fractions enriched in sarcolemma or in sarcoplasmic reticulum. No specific binding was found in mitochondria. These results indicate that the localization of [3H]nimodipine sites is not restricted to areas of the plasma membrane rich in beta-adrenoceptors, muscarinic receptors and sodium pump sites.

Effects of extracts of rat brain on the digitalis receptor.

There is a possibility that an endogenous substance exists which interacts with a ouabain binding site on Na+, K+-ATPase. Recently, several reports have appeared suggesting the presence of an endogenous digitalis-like substance in acid-acetone extracts of brain. We have demonstrated that in preparing an acid-acetone extract, peroxidized lipids and lysophospholipids are produced, both of which inhibit Na+, K+-ATPase, thereby complicating interpretation. Preliminary evidence suggests, however, that when rat brains are extracted with an aqueous-acetone mixture under nitrogen, a principle is obtained which specifically inhibits Na+, K+-ATPase.