Clinical features and outcome in childhood T-cell leukemia-lymphoma according to stage of thymocyte differentiation: a Pediatric Oncology Group Study

The immunophenotypes of lymphoblasts from children with newly diagnosed T-cell acute lymphoid leukemia (T-ALL, n = 101) or T-cell non-Hodgkin lymphoma (T-NHL, n = 31) were analyzed to correlate stage of thymocyte differentiation with clinical features and outcome. The 67 boys and 34 girls with T-ALL were 1 month to 18 years old (median, 8 years) with leukocyte counts ranging from 2 to 810 x 10(9)/L (median, 55 x 10(9)/L). Eighteen of these patients were black, and 70 had a mediastinal mass. Twenty-six boys and five girls with a median age of 9 years (range, 1 to 20 years) had T-NHL. Seven of these patients were black, and 24 had a mediastinal mass. The distributions of thymocyte developmental stages (early [CD7+], intermediate [CD1+ and/or CD4+ and/or CD8+], and mature [CD3+]) in cases of T-ALL and T-NHL were significantly different: 34%, 43%, and 23% v 6%, 62%, and 32% (P = .02). A comparison of the patients' clinical features according to the maturational stage of thymocytes failed to disclose significant differences in the majority of characteristics studied. However, patients with mature-stage T-NHL, with or without the addition of subjects with mature-stage T-ALL, were less likely to have a mediastinal mass (P = .02 for both comparisons). Those with intermediate-stage T-cell malignancy (T-ALL and T-NHL combined) were the subgroup most likely to have a mediastinal mass (P = .01). Response to remission induction therapy was significantly worse in the T-ALL subgroup with an early-stage phenotype: a failure rate of 21% v 0% and 6% for the two more differentiated phenotypic subgroups (P = .007). Event-free survival was not affected by thymocyte maturational stage in cases of either T-ALL or T-NHL. Despite evidence of clinical heterogeneity among the maturational stages of T-cell malignancies in children, these developmental subdivisions do not appear to be critical determinants of outcome once remission is achieved. We conclude that such phenotypes need not be included in the stratification plans for clinical trials using common induction treatment.     

Use of E mu-PIM-1 transgenic mice short-term in vivo carcinogenicity testing: lymphoma induction by benzo[a]pyrene, but not by TPA

E mu-pim-1 transgenic mice are predisposed to develop lymphomas. Due to their low spontaneous tumour incidence and their increased sensitivity towards the lymphomagen ethylnitrosourea these mice may present an interesting model for short-term carcinogenicity testing. Here, we report on the further exploration of this transgenic mouse model with two additional carcinogens known to have, among others, the lymphohaematopoietic system as target, i.e. benzo[a]pyrene (B[a]P) and 12-O-tetradecanoylphorbol-13-acetate (TPA). B[a]P, given three times a week (by gavage) for 13 weeks at 4.3, 13 or 39 mg/kg body weight, resulted in a dose-related increase in lymphomas up to a 90% incidence in E(mu)-pim-1 mice during the observation period of 40 weeks. B[a]P also induced tumours of the forestomach within this observation period, though at a lower incidence and apparently equally effective in wildtype and transgenic mice. TPA, on the other hand, was unable to induce lymphomas (or tumours in any other organ) in either transgenic or wildtype animals within the observation period of 44 weeks, when applied dermally at the maximum tolerated dose of 3 microg/mouse, twice a week for 35 weeks. Molecular analysis showed that B[a]P-induced lymphomas in transgenic mice were of T-cell origin, 80% of which had elevated levels of c-myc expression. None of the lymphomas had increased N-myc expression and mutation analysis of the ras-gene family revealed a K-ras mutation in only one out of eight tumours investigated. Also, none of the lymphomas showed aberrant expression of p53 as determined by immunohistochemistry. It is concluded that the E mu-pim-1 mouse model will not be very suitable for short-term carcinogenicity testing in general: only genotoxic chemicals that have the lymphohaematopoietic system as target for carcinogenesis in wild- type mice, appear to be efficiently identified.      

Histopathology and ultrastructural examination of optic nerve sheath biopsies after optic nerve sheath decompression with and without mitomycin

PURPOSE: We chose to compare histologically and ultrastructurally changes in the optic nerve sheath after optic nerve sheath decompression, initially after a second surgery and after treatment with mitomycin-C. The mechanism by which optic nerve sheath decompression alleviates papilledema can be further understood in consideration of the results. METHODS: Tissue was obtained by biopsy from 3 first-time surgical and 4 reoperative cases with and without mitomycin-C in patients with idiopathic intracranial hypertension. The sheaths were fixed in a mixture of 2% paraformaldehyde and 2% glutaraldehyde, osmicated and dehydrated in a series of ethanol, and finally embedded in epon. Tissue blocks were sectioned at 1 microm and stained with both PPD and toluidine blue. Thin sections were examined by transmission electron microscopy. RESULTS: Normal meningeal tissue obtained at the time at optic nerve sheath decompression consisted mainly of collagen, closely packed and roughly parallel to the axis of the optic nerve. Collagen deposition seen in scar tissue after secondary optic nerve sheath decompression was extremely disorganized and irregular, with the individual fibers laid down seemingly at random. There was little sense of layering or of parallel arrays. Mitomycin-C appeared to influence collagen deposition in such a way that the collagen was more regularly packed and more closely resembled unoperated tissue. CONCLUSIONS: The regular well-organized collagen packing seen in normal sheath tissue is disrupted and replaced by less organized but compact scar tissue after optic nerve sheath decompression. With mitomycin use, more regular collagen packing closely approximating that found in unoperated sheath occurs. This configuration of fibers lends support for the filtration mechanism of optic nerve sheath decompression in treating papilledema.     

The influence of slouching and lumbar support on iliolumbar ligaments, intervertebral discs and sacroiliac joints

OBJECTIVE: To investigate lumbopelvic kinematics when moving into a slouch. DESIGN: A biomechanical model was developed. Load tests in vitro verified the model. BACKGROUND: The precise mechanism causing disc herniation and back sprain is still debated. Most biomechanical studies have focused on lifting in a stooped posture. Previous studies address instability situations due to Euler buckling of the spine under axial load. However, no studies address lumbosacral, iliolumbar and sacroiliac kinematics in slouching, i.e. flexing the spine in situations with negligible compressive spinal load. METHODS: Modeling started with the click-clack movement, i.e. the transition from lumbar lordosis to lumbar kyphosis by the combination of backward rotation of the pelvis and ventral flexion of the spine. The flexed spine was compared with a crowbar which uses the iliolumbar ligaments as fulcrum and pivot. To analyse the click-clack movement in sitting, unembalmed erect human trunks were moved from a forward position to a backward position, recording angular changes between L5, sacrum and ilium. RESULTS: When moving the trunk stepwise backward with support at shoulder level, L5 showed forward rotation with respect to the sacrum, but rotation of the sacrum with respect to the iliac bones was reversed (i.e. counternutation). L5 showed displacement in ventral direction with respect to the ilium. Measurements were in agreement with prediction from the crowbar model of the spine. CONCLUSIONS: Backward rotation of the pelvis combined with flexion of the spine, i.e. slouching, results in backward rotation of the sacrum with respect to the ilium, dorsal widening of the intervertebral disc L5-S1 and strain on the iliolumbar ligaments when protection from back muscles against lumbar flexion is absent. Lumbar backrest support almost eliminates lumbosacral and sacroiliac movement. RELEVANCE: Understanding why the iliolumbar ligaments are loaded in slouching contributes to the understanding of the biomechanics of low back pain in everyday situations with small or negligible compressive spinal load. The results recommend lumbar support: backrests with free shoulder space.     

Pharmacological characterization of LPS and opioid interactions at the toll-like receptor 4

Background and Purpose

Previous work in our laboratory showed opioid agents inhibit cytokine expression in astrocytes. Recently, Watkins and colleagues hypothesized that opioid agonists activate toll-like receptor 4 (TLR4) signalling, which leads to neuroinflammation. To test this hypothesis, we characterized LPS and opioid effects on TLR4 signalling in reporter cells.

Experimental Approach

NF-κB reporter cells expressing high levels of TLR4 were used to compare LPS and opioid effects on NF-κB activation, a pathway activated by TLR4 stimulation.

Key Results

LPS increased TLR4 signalling in a concentration-dependent manner and was antagonized by LPS antagonist (LPS-RS, from Rhodobacter sphaeroides). A concentration ratio analysis showed that LPS-RS was a competitive antagonist. The opioid agonists, morphine and fentanyl, produced minor activation of TLR4 signalling when given alone. When tested following LPS stimulation, opioid agonists inhibited NF-κB activation but this inhibition was not blocked by the general opioid antagonist, naloxone, nor by the selective μ opioid receptor antagonist, β-FNA. Indeed, both naloxone and β-FNA also inhibited NF-κB activation in reporter cells. Further examination of fentanyl and β-FNA effects revealed that both opioid agents inhibited LPS signalling in a non-competitive fashion.

Conclusions and Implications

These results show that LPS-RS is a competitive antagonist at the TLR4 complex, and that both opioid agonists and antagonists inhibit LPS signalling in a non-competitive fashion through a non-GPCR, opioid site(s) in the TLR4 signalling pathway. If confirmed, existing opioid agents or other drug molecules more selective at this novel site may provide a new therapeutic approach to the treatment of neuroinflammation.