Use of a T cell-specific monoclonal antibody, T10B9, in a novel allogeneic stem cell transplantation protocol for hematologic malignancy high-risk patients.

To reduce the toxicity of traditional conditioning regimens for allogeneic stem cell transplantation (allo-SCT), we used single-agent chemotherapy conditioning with either busulfan (total cumulative dose, 16 mg/kg) or melphalan (200 to 240 mg/m 2 ), followed by the anti-T cell-specific monoclonal antibody T10B9 (MEDI-500) daily for 3 days. T cell-replete SCT was performed from HLA-identical sibling donors. Acute graft-versus-host disease (aGVHD) prophylaxis consisted of 7 additional days of T10B9 and delayed onset of cyclosporine (ie, on day +4 or +5). Twenty-six high-risk hematologic malignancy patients were entered onto this study. All 24 patients who survived longer than 8 days engrafted, although 1 patient experienced late graft failure. Deaths occurred in 21 of 26 patients because of infection (n = 7), progression/recurrence of primary disease (n = 6), aGVHD (n = 4), regimen-related toxicity (n = 1), and other causes (n = 3). Five of these patients are enjoying disease-free survival with a median survival of 1193 days after allo-SCT. The conditioning regimen induced modulation of surface expression of CD3 (but not CD4 or CD8) and was associated with decreasing tumor necrosis factor-alpha (but not interleukin-6) serum levels. In conclusion, single-agent chemotherapy conditioning with T10B9 produced durable engraftment and long-term survival in some patients who would not have qualified for a traditional allo-SCT.     

Influence of Malaria Infection on the Elaboration of Soluble Mediators by Adherent Mononuclear Cells

MALARIA RESULTS IN TWO SEEMINGLY PARADOXICAL PERTURBATIONS OF THE IMMUNE RESPONSE: polyclonal B-cell activation and immunosuppression. To determine what immunoregulatory role mediators secreted by adherent cells might play in these alterations, we cultured adherent cells from uninfected mice and from mice at different times during infection with Plasmodium berghei or P. yoelii. Culture supernatants obtained from these cells were tested for their ability to enhance the in vitro proliferative responses of thymocytes to suboptimal concentrations of concanavalin A or to inhibit the mitogen-stimulated proliferation of normal spleen cells. Supernatants obtained from adherent cells of mice early in infection (days 1 to 3) contained significantly elevated levels of enhancing activity which on Bio-Gel P-100 chromatography resembled lymphocyte-activating factor. Later in infection (days 4 and 5), these supernatants contained inhibitory activity. Normal adherent cells, when cocultivated in vitro with parasitized erythrocytes, ingested parasite debris and were stimulated to produce the enhancing factor. At high parasite/adherent-cell ratios, cells elaborated an inhibitory factor. These findings suggest that during malaria, adherent cells are converted from a nonspecific helper role to a nonspecific suppressor role. This modulation in function may be due to the direct interaction between adherent cells and parasitized erythrocytes.     

Distribution of hyaluronic acid and sulfated glycosaminoglycans during blood-vessel development in the chick chorioallantoic membrane

This study uses histochemical methods to determine the ultrastructural distribution of specific glycosaminoglycans (GAGs) during the development of blood vessels in the chick chorioallantoic membrane (CAM) and to correlate changes in GAG composition with the significant structural events in the development of these vessels. Tissues were stained with tannic acid, ruthenium red, and high iron diamine and digested in various GAG-degrading enzymes to identify specific GAGs. The results are consistent with a role for hyaluronic acid in the formation, alignment, or migration of the capillary plexus of the CAM and a role for sulfated GAGs (heparan sulfate, chondroitin sulfate, dermatan sulfate) in the differentiation and development of arterial and venous vessels of the chorioallantoic membrane.     

Gender differences in the association between cardiovascular reactivity and aggressive conduct.

The purpose of the present investigation was to examine the association between cardiovascular reactivity to provocation and physically and relationally aggressive conduct. Blood pressure and heart rate were assessed among seventy-seven 5th-grade participants during a period of rest and while discussing a relational provocation. In addition, teachers reported on participants' physically and relationally aggressive behavior. Results provided support for the hypothesis that heightened cardiac reactivity to provocation would be associated with relational forms of aggression among girls. In contrast, for boys, lower cardiac reactivity was associated with physical aggression. These results suggest that the association between cardiovascular reactivity and aggression differs for males and females and that reactivity following relational provocation may be an especially important predictor of relational aggression among girls. Implications for interventions among aggressive children are discussed.     

Prospective evaluation of the Gen-Probe assay for detection of Legionellae in respiratory specimens

A prospective evaluation of a DNA probe assay for detection ofLegionella species was performed on 427 consecutive respiratory specimens submitted over an 18-month period. The Gen-Probe assay utilizing both low (4.0) and high (>7.0) ratio threshold values was compared to direct fluorescent antibody staining (DFA) as a predictor of isolation ofLegionella on culture. The highest sensitivity (63 %) was obtained with the lower threshold ratio, but was not significantly different from the result obtained with a threshold ratio of >7.0 (50 %, p=0.722) or DFA results (44 %, p=0.479). The specificity of the DNA probe assay was improved with the high threshold (99 %) compared either to the low threshold ratio (95 %, p=0.0002) or DFA (97 %, p=0.055). When the DNA probe was compared to DFA and/orLegionella isolation on culture, a significantly lower specificity (97 % versus 99 %, p=0.0006) and higher sensitivity (74 % versus 37 %, p=0.013) was obtained with a threshold value of 4.0 than >7.0. Ten of 20 specimens with a DNA probe ratio between 4.0 and 7.0 were DFA positive, although only two were isolated on culture. The DFA assay and both probe threshold ratios have a high negative predictive value when compared to culture. However, only the threshold ratio of >7.0 has a sufficiently high positive predictive value to be useful alone. Although the DNA probe appears to be a practical alternative to DFA testing for the rapid diagnosis ofLegionella infections, false-negative results emphasize the importance of obtaining several specimens for testing, and confirm the fundamental role of culture in the diagnosis ofLegionella infections.     

Intramural distribution of adrenergic and cholinergic nerve fibers innervating arterioles of the hamster cheek pouch

Electron microscopic, autoradiographic and histochemical techniques were used to determine the distribution of adrenergic and cholinergic nerve fibers within the walls of arterioles having a width of 35 to 60 μ in the hamster cheek pouch. Nerves were confined to the adventitia and their varicose regions were distributed so that 86% were located within 1 μ of the media. Arterioles exposed to ³H-norepinephrine and examined by light microscopic autoradiography exhibited several sites of silver grain accumulation, as a result of the uptake of ³H-norepinephrine by adrenergic nerve fibers. In electron autoradiographs, approximately 70% of all adventitial nerve fibers exhibited silver grains and are therefore considered to be noradrenergic. The majority of all nerve-associated silver grains were located near the adventitial-medial junction. Smooth muscle cells sometimes possessed concentrations of silver grains above background levels, perhaps reflecting the capacity of these cells to take up norepinephrine. Acetylcholinesterase activity was demonstrated in 16 to 44% of the adventitial nerve fibers and they are presumed to be cholinergic. Acetylcholinesterase-stained fibers were distributed throughout the adventitia with 43% being located closer than 1 μ to the media. The morphological identification of a dual adrenergic and cholinergic innervation of arterioles of the hamster cheek pouch indicates the probable presence of an active as opposed to a passive vasodilatory mechanism.     

Immunohistochemical detection of c-erbB-2 protein in human benign and neoplastic prostate.

Both the polyclonal anti-c-erbB-2 peptide antiserum pAB 60 and the monoclonal anti-c-erbB-2 protein antibody mAB-1 detect the c-erbB-2 protein in human breast adenocarcinomas. We investigated c-erbB-2 expression in adult human benign hyperplastic and neoplastic prostates, using the avidin-biotin complex immunoperoxidase method. Formalin-fixed, paraffin-embedded specimens of benign hyperplastic prostate (13), prostatic adenocarcinoma (22), and prostatic adenocarcinoma lymph node metastases (two) were tested with pAB 60. Ten formalin-fixed, paraffin-embedded specimens of prostate adenocarcinoma, 11 frozen sections of benign hyperplastic specimens, and eight frozen sections of prostate adenocarcinoma were tested with mAB-1. Our results demonstrated consistent detection of c-erbB-2 immunohistochemically in frozen sections of both benign and malignant prostate. Preincubation of pAB 60 with the immunizing peptide blocked subsequent reactivity with prostatic tumor tissue, indicating specificity. However, fixation and processing protocols significantly affected the reactivity of the antigenic determinants detected by these antibodies, as mAB-1 was nonreactive with formalin-fixed, paraffin-embedded prostatic tissues. Differential reactivity of pAB 60 with malignant rather than benign glands was maximized by exposure of the specimen to the antibody at 4 degrees C rather than 22 degrees C. The most frequently observed staining pattern with both antibodies was cytoplasmic. However, mAB-1 produced distinctly membranous staining in two frozen specimens of benign hyperplasia and one specimen of prostate cancer.     

Association between Fruit and Vegetable Intakes and Mental Health in the Australian Diabetes Obesity and Lifestyle Cohort

Increasing prevalence of mental health disorders within the Australian population is a serious public health issue. Adequate intake of fruits and vegetables (FV), dietary fibre (DF) and resistant starch (RS) is associated with better mental and physical health. Few longitudinal studies exist exploring the temporal relationship. Using a validated food frequency questionnaire, we examined baseline FV intakes of 5845 Australian adults from the AusDiab study and estimated food group-derived DF and RS using data from the literature. Perceived mental health was assessed at baseline and 5 year follow up using SF-36 mental component summary scores (MCS). We conducted baseline cross-sectional analysis and prospective analysis of baseline dietary intake with perceived mental health at 5 years. Higher baseline FV and FV-derived DF and RS intakes were associated with better 5 year MCS (p < 0.001). A higher FV intake (754 g/d vs. 251 g/d, Q4 vs. Q1) at baseline had 41% lower odds (OR = 0.59: 95% CI 0.46–0.75) of MCS below population average (<47) at 5 year follow up. Findings were similar for FV-derived DF and RS. An inverse association was observed with discretionary food-derived DF and RS. This demonstrates the association between higher intakes of FV and FV-derived DF and RS with better 5 year mental health outcomes. Further RCTs are necessary to understand mechanisms that underlie this association including elucidation of causal effects.