Preliminary psychometric evaluation of the Child Health Ratings Inventory (CHRIs) and Disease-Specific Impairment Inventory-Hematopoietic Stem Cell Transplantation (DSII-HSCT) in parents and children.

PURPOSE: To describe the initial results of the Child Health Ratings Inventory (CHRIs), 20-item generic health-related quality of life (HRQL) instrument and the 10-item disease-specific (DS) module, the Disease Specific Impairment Inventory-Hematopoietic Stem Cell Transplantation (DSII-HSCT), for children and adolescents, ages 5-18 years and their parents following HSCT. STUDY DESIGN: Using cross sectional design, 122 children with a median age of 11 years (range 5.0-18 years) completed the questionnaire (CHRIs + DSII-HSCT) with research assistance. Seventy-four parents independently completed a parallel version of the questionnaire; health care providers assigned a global clinical severity rating. RESULTS: The generic core includes four domains: physical, role, and emotional functioning, and energy. The DS module has three domains: worry, hassles, and body image. The Cronbach's alpha for parents and for older children (8 years and over) exceeded 0.70 for all generic and DS domains. While the range of alpha coefficients was lower for younger children, ages 5-7 year, only the alpha coefficient for one domain (energy) was less than 0.70. The instrument satisfactorily discriminated between clinically important groups: those early in the transplant process (< 6 months) versus those later (> 12 months) and by provider-assigned clinical severity ratings. CONCLUSION: results suggest that the CHRIs generic core and its DSII-HSCT module is a promising measure of HRQL after pediatric HSCT. Although parent and child reports were moderately correlated and revealed complementary results, the unique perspectives of both raters provide a more complete picture of HRQL. Longitudinal application is underway to further characterize the measurement properties of the CHRIs and to determine the instrument's responsiveness and sensitivity to change over time in this vulnerable population.

Zolmitriptan orally disintegrating tablet is effective in the acute treatment of migraine.

A new formulation of zolmitriptan has been developed that dissolves on the tongue without the need for additional fluid intake. In this double-blind, parallel study, 471 patients were randomized to receive the zolmitriptan orally disintegrating tablet 2.5 mg (n=231) or matching placebo (n=240) to treat a single moderate or severe migraine. Headache relief following zolmitriptan 2.5 mg (63%) was significantly greater than with placebo (22%) at 2 h post-dose (primary endpoint; P < 0.0001). The zolmitriptan orally disintegrating tablet was also significantly more effective than placebo for 1-, 2- and 4-h pain-free response (8% vs. 3%, P=0.0207, 27% vs. 7%, P < 0.0001, and 37% vs. 11%, P < 0.0001, respectively). Of those patients stating a preference, 70% of patients preferred the orally disintegrating tablet to a conventional tablet. Zolmitriptan orally disintegrating tablets are an effective and convenient alternative to a conventional tablet, allowing migraine attacks to be treated anytime a migraine strikes, which can facilitate earlier treatment.

xid mice reveal the interplay of homeostasis and Bruton's tyrosine kinase-mediated selection at multiple stages of B cell development.

Human X-linked agammaglobulinemia (XLA) and murine X-linked immune defect (XID) are both immunodeficiencies mediated by mutations in Bruton's tyrosine kinase (Btk), yet the developmental stage(s) affected remain controversial. To further refine the placement of the XID defect(s), we used bromodeoxyuridine labeling to determine turnover, production and transition rates of developing B cell subsets in normal, xid and xid mice expressing a human Bcl-2 transgene (xid/bcl-2). We find the xid mutation manifest at two stages of B cell development. The first is early, reducing pre-B cell production by restricting pro-B to pre-B cell transit. Surprisingly, this impairment is offset by increased survival of cells progressing from the pre- to immature B cell pool, suggesting that Btk-independent homeostatic mechanisms act to maintain this compartment. The second point of action is late, substantially reducing mature B cell production. Together, these findings reconcile apparent discrepancies in the developmental stage affected by the murine versus human lesions and suggest previously unappreciated homeostatic processes that act at the pre-B to immature B cell transition. Finally, Btk likely functions differently at these two checkpoints, since ectopic Bcl-2 expression fails to directly complement the early xid lesion, yet reverses the defect impeding final B cell maturation.

B cell production and turnover in CBA/Ca, CBA/N and CBA/N-bcl-2 transgenic mice: xid-mediated failure among pre B cells is unaltered by bcl-2 overexpression.

The CBA/N strain carries xid, a murine btk missense mutation that reduces peripheral B cell numbers. Using in vivo BrdU labeling and cytofluorimetry, we have compared the magnitude, production rates, and turnover rates of each B lineage subset in the marrow and periphery of CBA/Ca and CBA/N mice. Our results show the pro-B compartment is largely unaffected by xid. In contrast, the pre-B cell pool is markedly reduced, reflecting a diminished production rate and unaltered turnover time. Despite diminished pre-B cell formation, the size of the immature B cell pool is relatively normal in CBA/N mice, due to increased proportional survival of pre-B cells. In addition, we have assessed the marrow and peripheral B cell subsets of CBA/N mice transgenic for bcl-2. These results indicate that while the bcl-2 transgene promotes lengthened survival in most B cell subsets, the pro/pre-B cell losses mediated by xid are not abrogated by bcl-2 overexpression. Taken together, these findings suggest that the initial [not readable: see text] from the pro- to pre-B cell pools, and that anomalies in subsequent compartments likely reflects the action of homeostatic mechanisms compensating for compromised pre-B cell production.

Expression of the Bcl-2 family member A1 is developmentally regulated in T cells.

During T cell development, cells that fail to meet stringent selection criteria undergo programmed cell death. Thymocyte and peripheral T cell susceptibility to apoptosis is influenced by expression of Bcl-2 family members, some of which are expressed in a developmentally patterned manner. We previously showed developmentally regulated expression of A1, an anti-apoptotic Bcl-2 family member, among B cell developmental subsets. Here we show that cells of the T lineage also express A1 in a developmentally regulated manner. Both A1 mRNA and A1 protein are readily detectable in the thymus, and while present among DN cells, A1 mRNA is up-regulated to very high levels among double-positive (DP) thymocytes. It is then down-regulated to moderate levels among single-positive (SP) thymocytes, and finally expressed at approximately 25-fold lower levels among mature SP CD4(+) and CD8(+) lymph node T cells than among DP thymocytes. Furthermore, we find that in vitro TCR ligation up-regulates A1 expression among both DP and SP thymocytes. Together, these data show that A1 expression is developmentally regulated in T lymphocytes and is responsive to TCR signaling, suggesting that A1 may play a role in maintaining the viability of DP thymocytes.

Health-related quality of life in pediatric bone marrow transplant survivors: according to whom?

Historically, health-related quality of life (HRQL) assessment in pediatrics, including the few validated instruments in pediatric oncology, has been based on proxy reporting, relying primarily on parental assessment. Children have been deemed incapable of providing consistent and reliable information about their level of functioning or state of well-being. Previous studies have been hampered by either limited or poor correlation among the proxy reporters, i.e., teachers, parents and physicians, and in comparisons to disease severity. Simply stated, proxy reporters have greater agreement about what the child can do vs. what the child thinks or feels. Comparisons among proxy reporters have been hindered also by a lack of parallel content in the instruments used, which may result in poorly congruent assessments simply because the instruments measure different constructs. In addition to the measurement issues, the emotional milieu of the parent, particularly the mother, has been shown to influence assessments of the child's functioning. Maternal distress, marital adjustment and health locus of control all co-vary with reports of the child's behavior. What, then, is the proxy reporter telling us about the child? We conducted a cross-sectional study of school-aged pediatric bone marrow transplant (BMT) patients at our institution to evaluate children's self-reported HRQL and functional status. We formally tested the Child Health Rating Inventories (CHRIs), a recently developed generic health-status measure, with its companion measure, the Disease Impairment Inventories-Bone Marrow Transplant (DSII-BMT). Separate questionnaires were administered to patients, parents and physicians at a scheduled outpatient visit after BMT. The questionnaires were designed to have parallel content. All responses were confidential. The psychometric properties of the CHRIs and DSII-BMT are reported elsewhere. In brief, the responses of all raters were reliable, based on measurements of internal consistency. The children's self-reported health status was correlated significantly with the physicians' disease severity rating (DSR) across all generic and disease-specific domains. In contrast, parental reports of child health status were not correlated significantly with the DSR for disease-specific problems or the child's pain. Parental ratings deviated most from the children's ratings within the dimensions of mental health and quality of life (p < 0.001). For the entire sample, parental ratings were significantly lower than the children's ratings. Within the subgroup "early after transplant (<6 months)", parental ratings were significantly lower than the children's self-reports in all categories. In the subgroup ">12 months after transplant", with the exception of mental health and quality of life, parental scores were the same as or higher than the children's ratings. Our results confirm previous studies that the parental reporting of children's health status is a complex construct and that valuable information can be elicited directly from the children. Further research is needed to substantiate these findings, particularly in longitudinal applications with adequate sample sizes.

Phase 1 human trial of adenosine-potassium cardioplegia.

BACKGROUND: The cardioprotective role of adenosine in various models of ischemia-reperfusion, including adenosine supplementation to cardioplegic formulations, has been studied extensively. The appropriate dose of adenosine in humans is uncertain and could be limited by systemic hypotension or AV block. METHODS AND RESULTS: An open-label, nonrandomized phase 1 adenosine dose-ranging study was performed. Patients scheduled for primary isolated coronary bypass surgery were eligible for the study. Antegrade warm blood potassium cardioplegia (ratio, 4:1, blood to crystalloid) was administered in the routine fashion, with adenosine added to the initial 1000-mL dose and final 500-mL dose. Patients were studied in blocks of 4 per concentration. An escalating adenosine dosage schedule was planned to produce blood cardioplegia concentrations from 0 to 250 mumol/L, and the blocks were tested sequentially. Stopping rules were defined for systemic hypotension (phenylephrine dose during cardiopulmonary bypass > or = 5.0 mg; phenylephrine dose during cardioplegic induction > or = 800 micrograms) and AV block (permanent pacemaker insertion; temporary pacing dependency for > 90 minutes after cardiopulmonary bypass). Doses of 1, 2.5, 5, 10, and 25 mumol/L were well tolerated. With 50 mumol/L, systemic hypotension occurred during cardioplegic induction in 3 of 4 patients versus 1 of 24 (P < .005) at all lower concentrations (880 +/- 217 versus 297 +/- 286 micrograms phenylephrine per patient). The studies were repeated with an 8:1 blood-to-crystalloid cardioplegia delivery system. Adenosine concentrations of 0 (n = 4), 15 (n = 12), 20 (n = 8), and 25 mumol/L (n = 4) were tested. Hypotension during cardioplegic induction was more prevalent (P = .05) with the higher doses (15 mumol/L, 394 +/- 189 micrograms, 1 of 12 patients; 20 mumol/L, 360 +/- 355 micrograms, 2 of 8 patients; 25 mumol/L, 600 +/- 478 micrograms, 2 of 4 patients). There were no differences with respect to systemic hypotension during cardiopulmonary bypass or for pacing > 90 minutes after discontinuation of cardiopulmonary bypass, and no patient required permanent pacing. There have been no deaths, Q-wave myocardial infarctions, intra-aortic balloon pump insertions, or cerebral infarctions in the total sample of 56 patients. CONCLUSIONS: Our initial investigations have shown that adenosine can be safely administered during cardiopulmonary bypass. The authors recommend that further studies are warranted using adenosine 15 to 25 mumol/L, depending on the delivery system.

The anticonvulsant effects of vitamin E: a further evaluation.

Vitamin E (d-alpha-tocopherol) has proven to be a useful adjunct to anticonvulsant drugs in clinical studies. Improvement has occurred even in patients with complex partial seizures, which are often resistant to drug therapy. In animals, vitamin E is effective against ferrous chloride seizures, hyperbaric oxygen seizures and penicillin-induced seizures. It has failed, however, to show anticonvulsant effects in the standard animal models used for drug screening--the maximal electroshock and threshold pentylenetetrazol tests. The present experiments were designed to further explore the anti-epileptic actions of vitamin E in animals. Three models related to complex partial epilepsy were used: 1) the development of amygdala-kindled seizures; 2) the development of electrically-induced status in kindled animals; and 3) the development of kainic-acid seizures. Vitamin E failed to produce significant effects in any of the models.

An evaluation of the anticonvulsant effects of vitamin E.

The anticonvulsant effects of D-alpha-tocopherol (vitamin E) were studied in 4 animal seizure models: the Metrazol threshold model (MET), the maximal electroshock model (MES), the kindling model (well-established seizures), and the ferrous chloride model. Vitamin E failed to antagonize seizures in the MES, MET, or the kindling models. It was, however, able to significantly delay the onset of electrographic seizures in the intracerebral ferrous chloride model. Thus, vitamin E shows activity in the ferrous chloride model, but not in the animal models commonly used to screen for anticonvulsant drug actions.