Intercellular adhesion molecule-1 mediates the expression of monocyte- derived MIP-1 alpha during monocyte-endothelial cell interactions

The extravasation of leukocytes from the lumen of the vessel to a site of inflammation initially requires a specific binding event followed by migration of the cells through the endothelial cell layer into the inflammatory foci. The interaction of leukocytes with the endothelium via specific receptors may provide intracellular signals that activate the cells. In the present study we have investigated the production of MIP-1 alpha, a mononuclear cell chemotactic protein, during monocyte:endothelial cell interactions. Neither unstimulated nor interferon (IFN)-stimulated human umbilical vein endothelial cells (HUVECs) produced substantial MIP-1 alpha protein. However, the addition of enriched monocyte populations with unstimulated HUVECs resulted in the production of MIP-1 alpha. Monocytes cultured with IFN- gamma-activated HUVECs showed an additional increase in MIP-1 alpha production. Immunohistochemical analysis demonstrated that the monocyte was the cellular source of MIP-1 alpha production in this coculture system. The mechanism of MIP-1 alpha expression was further assessed by determining the role of adhesion molecules in the regulation of MIP-1 alpha production during monocyte:HUVEC interactions. To attenuate the increased production of MIP-1 alpha by the monocyte:HUVEC interaction, anti-adhesion molecule monoclonal antibodies (MoAbs) were added to the cultures. Addition of anti-ICAM-1 neutralizing MoAbs significantly inhibited the production of MIP-1 alpha, whereas neutralizing anti-VCAM- 1 MoAbs failed to block MIP-1 alpha production. Furthermore, MIP-1 alpha production was induced in monocytes cultured on ICAM-1-coated plates. These results indicate an intimate relationship between leukocyte-endothelial cells, adhesion molecule, and the expression of the monocyte-derived chemokine MIP-1 alpha during cellular adhesion. This mechanism may serve an important role in cell activation and recruitment of leukocytes during the initiation of an inflammatory response.     

High glucocorticoid receptor content of leukemic blasts is a favorable prognostic factor in childhood acute lymphoblastic leukemia

We have previously shown that the number of glucocorticoid receptors (GR) per cell in malignant lymphoblasts from children with newly diagnosed pre-B- and early pre-B-cell acute lymphoblastic leukemia (ALL) has a positive correlation with the probability of successful remission induction (Quddus et al, Cancer Res, 45:6482, 1985). We report now on the long-term outcome for these patients treated on a single protocol with 3 different treatment arms, all of which included glucocorticoid pulses during maintenance therapy. GR were quantitated in leukemic cells from 546 children with ALL at the time of diagnosis. Immunophenotyping studies were performed on all specimens. Prior studies showed that in pre-B- and early pre-B-cell ALL, successful remission induction was associated with a median GR number of 9,900 sites/cell, whereas induction failure was associated with a median receptor number of 4,800 sites/cell. Long-term follow-up of these patients shows an association between higher GR number and improved prognosis. The 5-year event-free survival of 61.0% (SE 2.8%) for patients whose leukemic cells had greater than 8,000 receptors/cell and 47.3% (SE 3.3%) for those with less than 8,000 receptors/cell is significantly different (P < .001). This difference remains significant when adjusted multivariately for blast immunophenotype and clinical risk factors (P < .001) or for treatment type (P < .001). We conclude that GR number greater than 8,000 sites/leukemic cell is a favorable prognostic marker for children with acute lymphocytic leukemia. This finding offers deeper insights into molecular mechanisms of anti- leukemia therapy and suggests that manipulation of steroid receptor number might augment the antitumor response, thus opening new avenues for basic and clinical research.     

Recombinant human interleukin-1 receptor antagonist protects early myeloid progenitors in a murine model of cyclophosphamide-induced myelotoxicity

Expression of hematoregulatory cytokines such as interleukin-1 (IL-1) in response to cytotoxic chemotherapy hastens hematopoietic recovery, but may also potentiate myelotoxicity if myeloid progenitors enter cell cycle before drug clearance. In the present study, the ability of recombinant human IL-1 receptor antagonist (IL-1ra) to protect hematopoietic progenitors was studied in a murine model of cyclophosphamide (CPA)-induced myelotoxicity. CF-1 female mice received 200 mg/kg CPA and either 10 mg/kg IL-1ra or an equal volume of 0.05% human serum albumin (HSA) intraperitoneally (i.p.), followed 12 hours later by IL-1ra or HSA. CPA and IL-1ra increased absolute neutrophil counts (ANCs) at days 2 (P = .001) and 14 (P = .0025) after CPA. In IL- 1ra-treated mice, colony-forming units granulocyte-macrophage (CFU- GM)/tibia were increased twofold and threefold at days 2 (P = .0047) and 7 (P = .023), respectively, whereas high proliferative potential colony-forming cells (HPP-CFC)/tibia were decreased twofold to threefold at 8 hours (P = .039) and 24 hours (P = .0033), but were approximately threefold higher than HSA-treated mice at day 7 after CPA. Coadministration of CPA and IL-1 enhanced myelotoxicity compared with mice injected with CPA and IL-1ra or HSA. In vivo, IL-1ra protected HPP-CFC, but not CFU-GM, from hydroxyurea suicide after a single dose of CPA, suggesting that IL-1ra inhibited cycling of HPP- CFC. In vitro, IL-1ra did not alter proliferation of CFU-GM, but inhibited IL-1-enhanced proliferation of HPP-CFC. These data suggest that IL-1ra acts as an indirect negative regulator of hematopoiesis and protects HPP-CFC from CPA, possibly by inhibiting IL-1-enhanced proliferation of early myeloid progenitors.     

Late,not early mismatch responses to changes in frequency are reduced or deviant in children with dyslexia: an event-related potential study

Background

Developmental disorders of oral and written language have been linked to deficits in the processing of auditory information. However, findings have been inconsistent, both for behavioural and electrophysiological measures.

Methods

In this study, we examined event-related potentials (ERPs) in 20 6- to 14-year-old children with developmental dyslexia and 20 age-matched controls, divided into younger (6–11 years, n = 10) and older (11–14 years, n = 10) age bands. We focused on early (mismatch negativity; MMN) and late (late discriminative negativity; LDN) conventional mismatch responses and associated measures derived from time-frequency analysis (inter-trial coherence and event-related spectral perturbation). Responses were elicited using an auditory oddball task, whereby a stream of 1000-Hz standards was interspersed with rare large (1,200 Hz) and small (1,030 Hz) frequency deviants.

Results

Conventional analyses revealed no significant differences between groups in the size of the MMN to either large or small frequency deviants. However, the younger age band of children with dyslexia showed an enhanced inter-trial coherence in the theta frequency band over the time window corresponding to the MMN to small deviants. By contrast, these same children showed a reduced-amplitude LDN for the small deviants relative to their age-matched controls, whilst the older children with dyslexia showed a shorter and less intense period of event-related desynchronization over this time window.

Conclusions

Initial detection and discrimination of auditory frequency change appears normal or even enhanced in children with dyslexia. Rather, deficits in late-stage auditory processing appear to be a feature of this population.     

Placental weight, birth measurements, and blood pressure at age 8 years

OBJECTIVE: To examine relationships between blood pressure during childhood and both placental weight and body size at birth, in an Australian population. DESIGN: A follow up study of a birth cohort, undertaken when cohort members were aged 8 years. SETTING: Adelaide, South Australia. SUBJECTS: 830 children born in the Queen Victoria Hospital in Adelaide, South Australia, during 1975-6. MAIN OUTCOME MEASURES: Systolic and diastolic blood pressure measured when the children were aged 8 years. RESULTS: Blood pressure at 8 years was positively related to placental weight and inversely related to birth weight, after adjusting for the child's current weight. For diastolic pressure there was a decrease of 1.0 mm Hg for each 1 kg increase in birth weight (95% confidence interval (CI) = -0.4 to 2.4) and an increase of 0.7 mm Hg for each 100 g increase in placental weight (95% CI = 0.1 to 1.3). Diastolic pressure was also inversely related to chest circumference at birth, independently of placental weight, with a decrease of 0.3 mm Hg for each 1 cm increase in chest circumference (95% CI = 0.2 to 0.5). CONCLUSIONS: These findings are further evidence that birth characteristics, indicative of fetal growth patterns, are related to blood pressure in later life.