Blood and Marrow Transplant Clinical Trials Network State of the Science Symposium 2007.

Outcomes of hematopoietic cell transplantation are steadily improving. New techniques have reduced transplant toxicities, and there are new sources of hematopoietic stem cells from unrelated donors. In June 2007 the Blood and Marrow Transplant Clinical Trials Network convened a State of the Science Symposium of more than 200 participants in Ann Arbor to identify the most compelling clinical research opportunities in the field. This report summarizes the symposium's discussions and identifies eleven high priority clinical trials that the network plans to pursue over the course of the next several years.     

Hyperthermia and maximal oxygen uptake in men and women

To compare the effect of hyperthermia on maximal oxygen uptake (O_2max) in men and women, O_2max was measured in 11 male and 11 female runners under seven conditions involving various ambient temperatures (T_a at 50% RH) and preheating designed to manipulate the esophageal (T_es) and mean skin temperatures at O_2max. The conditions were: 25°C, no preheating (control); 25, 35, 40, and 45°C, with exercise-induced preheating by a 20-min walk at ~33% of control O_2max; 45°C, no preheating; and 45°C, with passive preheating during which T_es and were increased to the same degree as at the end of the 20-min walk at 45°C. Compared to O_2max (l·min^–1) in the control condition (4.52±0.46 in men, 3.01±0.45 in women), O_2max in men and women was reduced with exercise-induced or passive preheating and increased T_a, ~4% at 35°C, ~9% at 40°C and ~18% at 45°C. Percentage reductions (7–36%) in physical performance (treadmill test time to exhaustion) were strongly related to reductions in O_2max (r=0.82–0.84). The effects of hyperthermia on O_2max and physical performance in men and women were almost identical. We conclude that men and women do not differ in their thermal responses to maximal exercise, or in the relationship of hyperthermia to reductions in O_2max and physical performance at high temperature. Data are reported as mean (SD) unless otherwise stated.     

Age-dependent increase of peritoneal B-1b B cells in SCID mice

The impact of increasing age upon immunoglobulin production and B-lymphocyte generation in "leaky" severe combined immune-defective (SCID) mice was examined by enzyme-linked immunosorbent assay and flow cytometry. By 1 year of age, the mice had normal numbers of B cells in their peritoneal cavity, while their spleen had very few immunoglobulin M-positive (IgM+) cells. The majority of B cells expressed the CD11b marker characteristic of the B-1b subset. B-1a (CD5+) cells were present at a lower frequency and B-2 cells were absent. The frequency of mice producing detectable immunoglobulin increased with age, and isotype diversity within individual mice was variable. IgM production was most frequently observed followed by IgG3 and IgG2a, then IgG1, and finally IgA. The selective persistence of the B-1 B-cell subset in the peritoneal cavity of aging SCID mice is a natural model for the study of those genetic and environmental influences that determine lymphocyte longevity.     

Genomic screen for loci associated with alcohol dependence in Mission Indians.

Alcohol dependence is a leading cause of morbidity and mortality in Native Americans, yet biological factors underlying the disorder in this ethnic group remain elusive. This study's aims were to map susceptibility loci for DSM-III-R alcohol dependence and two narrower alcohol-related phenotypes in Mission Indian families. Each participant gave a blood sample and completed an interview using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) that was used to make alcohol dependence diagnoses and the narrower phenotypes of withdrawal, and drinking severity. Genotypes were determined for a panel 791 microsatellite polymorphisms. Analyses of multipoint variance component LOD scores for the dichotomous DSM-III-R phenotype revealed no peak LOD scores that exceeded 2.0 at any chromosome location. Two chromosomes, 4 and 12, had peak LOD scores that exceeded 2 for the alcohol use severity phenotype and three chromosomes 6, 15, 16 were found to have peaks with LOD scores that exceeded 2 for the withdrawal phenotype. Evidence for linkage to chromosomes 4 and 15, and 16 have been reported previously for alcohol related phenotypes whereas no evidence has as yet been reported for chromosomes 6 and 12. Combined linkage and association analysis suggest that alcohol dehydrogenase 1B gene polymorphisms are partially responsible for the linkage result on chromosome 4 in this population. These results corroborate the importance of several chromosomal regions highlighted in prior segregation studies in alcoholism and further identify new regions of the genome that may be unique to either the restricted phenotypes evaluated or this population of Mission Indians.     

Twice weekly prophylactic therapy in haemophilia A.

Factor VIII-containing materials were administered to four severely affected haemophiliacs twice weekly in doses calculated to raise the factor VIII level to either 15% or 30% of average normal. The pooled results from those patients with statistically similar baseline bleeding frequencies showed a significant reduction in bleeding frequency on both doses in the first 48 hours. The 30% dose produced a more significant reduction than the 15% dose in the first 24 hours, but there was no significant difference between the two doses in the second 24 hours. It appears that to reduce the bleeding frequency of severely affected haemophiliacs by 60% would require a two-and-a-half-fold increase in therapeutic materials. A 90% reduction would need nine times the amount of material currently in use.     

Effect of magnesium on sodium transport in toad urinary bladder.

Voltage-clamp techniques were employed to examine the effect of magnesium (Mg) on sodium transport in the isolated urinary bladder of the Dominican toad. Substitution of 1 mM Mg had no effect, but 3-mM Mg substitution resulted in a reversible increase in short-circuit current (27%) and potential difference (19%) and decrease in transepithelial resistance (14%); no greater effect was seen with 5- or 10-mM Mg substitution. The effect was produced by mucosal or mucosal and serosal Mg substitution; serosal Mg substitution was without effect. Analysis of electrical parameters disclosed that magnesium increased net sodium transport via an effect on the sodium pump.     

The histologic border zone of acute myocardial infarction--islands or peninsulas?

Observation of isolated islands of apparently surviving myocardium within areas of necrotic tissue at the edge of myocardial infarctions has been interpreted by some as histologic evidence of a unique "border zone" region. Serial section reconstruction of transmural canine myocardial infarctions was performed in this study to establish whether these islands were truly isolated or were continuous peninsulas of tissue separated by the plane of section. Three-dimensional analysis of the infarcts revealed no true islands but instead demonstrated a region composed of highly complex interdigitating peninsulas. We conclude that there is an extremely irregular but sharp boundary demarcating normal and infarcted myocardium with no intermediate zone. This observation is discussed in relation to recent data, based on coronary blood flow and creatine phosphokinase analysis, which also demonstrates a sharp boundary between the normal and infarct zones.     

A canine model for reaginic hypersensitivity and allergic bronchoconstriction

Immunization of neonatal dogs with a conjugate of 2,4-dinitrobenzene and ovalbumin (DNP₂-OA), using aluminum hydroxide as the adjuvant, elicited long-lasting (over 30 wk) anti-DNP and anti-OA IgE antibody responses of high titers as determined by homologous passive cutaneous anaphylaxis. Low antigen doses of 10 or 50 μg were more effective than the higher doses of 250 or 1,250 μg in inducing high IgE antibody levels. However, this method of immunization failed to elicit any detectable IgE antibody response in adult dogs. Bronchoprovocation with antigen of sensitized animals having IgE antibody titers in excess of 64 resulted in a marked increase in airflow resistance, which could be corrected by the administration of nebulized isoproterenol. On the other hand, sensitized animals with IgE antibody titers in the order of 64 did not manifest significant bronchoconstriction on inhalation challenge but developed anaphylaxis following intravenous injection of the antigen.     

CD40 signaling regulates innate and adaptive activation of microglia in response to amyloid beta-peptide

Although deposition of amyloid beta-peptide (Abeta) as Abeta plaques involves activation of microglia-mediated inflammatory responses, activated microglia ultimately fail to clear Abeta plaques in the brains of either Alzheimer's disease (AD) patients or AD mouse models. Mounting evidence suggests that chronic microglia-mediated immune response during Abeta deposition etiologically contributes to AD pathogenesis by promoting Abeta plaque formation. However, the mechanisms that govern microglia response in the context of cerebral Abeta/beta-amyloid pathology are not well understood. We show that ligation of CD40 by CD40L modulates Abeta-induced innate immune responses in microglia, including decreased microglia phagocytosis of exogenous Abeta(1-42) and increased production of pro-inflammatory cytokines. CD40 ligation in the presence of Abeta(1-42) leads to adaptive activation of microglia, as evidenced by increased co-localization of MHC class II with Abeta. To assess their antigen-presenting cell (APC) function, cultured microglia were pulsed with Abeta(1-42) in the presence of CD40L and co-cultured with CD4(+) T cells. Under these conditions, microglia stimulate T cell-derived IFN-gamma and IL-2 production, suggesting that CD40 signaling promotes the APC phenotype. These data provide a mechanistic explanation for our previous work showing decreased microgliosis associated with diminished cerebral Abeta/beta-amyloid pathology when blocking CD40 signaling in transgenic Alzheimer's mice.     

The development of a Pharmacy Student Work Values Inventory (PSWVI).

The purpose of this study was to develop an instrument that measures pharmacy student work values. The instrument was included in a questionnaire mailed to 1,820 pharmacy students who had just graduated or were in their last year of pharmacy school from 19 schools of pharmacy nationwide. A total of 738 questionnaires were deemed usable for a usable rate of 41.5 percent. After Varimax factor analysis, eleven reliable factors emerged: Quality Patient Care; Supervision and Company Policy; Work Creativity/Variety; Status; Management/Leadership; Economic Return; Work Schedule; Family Responsibilities; Job Security; Co-worker Relationships; and Policies and Procedures. "Job Security," "Family Responsibilities," and "Patient Care" were rated least and negatively important respectively. There were no differences between BS and PharmD degree aspirants on the eleven factors; however, there were some significant differences between sexes. Women rated "Supervision and Company Policy" and "Quality Patient Care" higher than men. Men did not negatively value "Work Schedule" as much as women did, i.e., women preferred to work traditional, weekday hours.