Treatment related deaths during induction and in first remission in acute lymphoblastic leukaemia: MRC UKALL X

The benefits of achieving a long term event free survival of 60-70% by using increasingly intense treatment regimens must be weighed against the increased risk of treatment toxicity. From 1985 to 1990, 1612 children with childhood acute lymphoblastic leukaemia (ALL) in the UK were treated on MRC UKALL X with intensive induction therapy, central nervous system directed therapy (cranial irradiation and intrathecal methotrexate), and continuing treatment for two years. There was a randomisation to receive blocks of additional intensification treatment at five weeks, 20 weeks, not at all, or both. The five year disease free survival was 71% for children randomised to two blocks of intensification, a 14% improvement on children randomised to no intensification treatment. Treatment related mortality in this national multicentre study has been analysed for induction and first remission (including those after intensification treatment). There were 38 induction deaths, 2.3% and 53 deaths in first remission, 3.3% (including those from a second malignancy). Thirty one (84%) of the induction deaths followed an infection: bacterial in 22 and fungal in nine. Thirty seven infective remission deaths occurred: bacterial in 11, viral in 16, fungal in seven, and three caused by Pneumocystis carinii pneumonia. Ten of these deaths followed a block of intensification treatment. The majority of noninfective remission deaths followed the development of a second tumour. Risk analysis for an induction death showed girls and children with Down's syndrome to be at greater risk. For deaths in first remission analysis showed an increased risk for bone marrow transplant (BMT) patients and children with Down's syndrome. There was no effect of age and leucocyte count for either group. Most significantly when BMT patients were excluded from the analysis, intensification treatment did not increase the risk of remission death.     

5-HYDROXYTRYPTAMINE-INDUCED CONTRACTION OF THE MARMOSET AORTA IS MEDIATED BY A 5-HT1-LIKE RECEPTOR

1. 5-Hydroxytryptamine (5-HT) exerts both contractile and relaxant effects in the marmoset isolated aorta, actions that are unaffected by the 5-HT₂ antagonist ketanserin. The aim of the present study was to define the receptors mediating the contractile activity of 5-HT in the marmoset aorta.
2. Contractile responses were elicited in aortic rings that were either: (i) precontracted submaximally with the thromboxane A₂ agonist U44069 in order to amplify the responses; or (ii) exposed to N ^ω-nitro- L -arginine (100 μmol/L) plus LY 53857 (0.1 μmol/L; a 5-HT₂ receptor antagonist shown previously to inhibit relaxation). The effect of 5-HT on adenosine 3',5'-cyclic monophosphate (cAMP) formation was also investigated.
3. The effects of agonists and antagonists comprised: (i) agonist potencies in the order 5-carboxamidotryptamine > 5-HT > sumatriptan > 8-hydroxy-2-(di- n -propylamino)tetralin; (ii) inhibition of contractile action of 5-HT by the 5-HT_1D antagonist GR 127935; (iii) a contractile response to methysergide; (iv) a lack of effect of tropisetron, an antagonist of 5-HT₃ and 5-HT₄ receptors; and (v) inhibition of forskolin-stimulated cAMP formation by 5-HT (in the presence of LY 53857), indicative of negative coupling to adenylate cyclase.
4. The above effects fulfil the criteria for a 5-HT₁-like receptor. In view of the previous finding that this contractile response is insensitive to ketanserin, it is concluded that the contractile effects of 5-HT in the marmoset aorta are mediated exclusively by a 5-HT₁-like receptor.     

Mine Blast Injuries - Our Experience

Background

The sudden increase in incidence and magnitude of mine blast injuries prompted us to highlight the problem and its management.

Methods

The cases of mine blast injuries occurring during mining and demining in a particular geographical area were analysed. Total 27 cases of mine blast injuries occurred during mining or demining operations in a period of 13 months.

Results

Various body regions were involved in the mine blast injuries but the main brunt was borne by feet and legs followed by multiple body regions due to splinters. 14 patients underwent below knee (BK) amputation while 4 patients required through knee (TK) amputations. The effect of blast was so severe that most of the cases required 2 to 5 times wound debridements. The initial aggressive debridement / open stump amputation saved the limb and life of all patients.

Conclusion

A mine blast causes extensive injuries and psychological trauma. Management is needed urgently, surgery is difficult, and amputation is often inevitable. Maximum lives and limbs can be saved with aggressive debridement, repeated inspections and dressings under anaesthesia and definitive closure at optimum time.Key Words: Amputation, Antipersonnel mine, Crush syndrome, Debridements, Mine blast injury, Secondary missiles, Shrapenels     

Effect of cyclical mechanical stretch and exogenous transforming growth factor-beta1 on matrix metalloproteinase-2 activity in lamina cribrosa cells from the human optic nerve head

PURPOSE: Extensive remodeling of the lamina cribrosa extracellular matrix occurs in primary open angle glaucoma. The transforming growth factor-beta (TGF-beta) and matrix metalloproteinase (MMP) protein families are implicated in this process. The authors investigated (a). the effect of cyclical mechanical stretch on TGF-beta1 mRNA synthesis, TGF-beta1 protein secretion, MMP-2 protein activity and (b). the effect of exogenous TGF-beta1 on MMP-2 protein activity in human lamina cribrosa cells in vitro. METHODS: Primary human lamina cribrosa cells grown on flexible and rigid plates were exposed to cyclical stretch (1Hz, 15%) or static conditions for 12 and 24 hours. Cells grown on 100-mm plates were exposed to human TGF-beta1 (10 ng/ml) or vehicle (4 mM HCl/1% BSA) for 24 hours. TGF-beta1 mRNA synthesis in stretched and static cells was measured using real-time polymerase chain reaction. TGF-beta1 protein secretion in stretched and static cell media was measured using enzyme linked immunosorbent assay. Gelatin zymography measured MMP-2 activity in stretched, static, TGF-beta1- treated and vehicle-treated cell media. RESULTS: Cyclical stretch induced significant increases in TGF-beta1 mRNA synthesis after 12 hours (**P < 0.01) and TGF-beta1 protein secretion after 24 hours (*P < 0.05). Cyclical stretch significantly (*P < 0.05) increased MMP-2 activity in cell media after 24 hours. Exogenous TGF-beta 1 induced a significant (**P < 0.01) increase in cell media MMP-2 activity after 24 hours. CONCLUSIONS: These results suggest that cyclical stretch and TGF-beta1 modulate MMP-2 activity in human lamina cribrosa cells. TGF-beta 1 and MMP-2 release from lamina cribrosa cells may facilitate matrix remodeling of the optic nerve head in primary open angle glaucoma.     

Optimal suppression of thromboxane A(2) formation by aspirin during percutaneous transluminal coronary angioplasty: no additional effect of a selective cyclooxygenase-2 inhibitor

OBJECTIVES: We examined the contribution of cyclooxygenase (COX)-1 and -2 to the generation of prostacyclin, thromboxane (Tx) A(2), and 8-epi prostaglandin (PG) F(2alpha) during percutaneous transluminal coronary angioplasty (PTCA). BACKGROUND: Both TxA(2) and 8-epi PGF(2alpha) activate platelets and are mitogenic, whereas prostacyclin is a platelet inhibitor, and therefore may influence the outcome of PTCA. METHODS: Twenty-one patients undergoing PTCA while receiving aspirin 300 mg daily or aspirin plus the selective COX-2 inhibitor nimesulide were compared with 13 patients treated only with fradafiban, a glycoprotein IIb/IIIa antagonist. Urine was analyzed for the metabolites of TxA(2) (Tx-M) and prostacyclin (PGI-M) and for the isoprostane, 8-epi PGF(2alpha). RESULTS: In the fradafiban group, there was a marked increase in Tx-M during PTCA (mean, 1973; 95% confidence interval [CI] 112 to 3834 rising to mean 7645; 95% CI 2,009 to 13281 pg/mg creatinine, p = 0.018). The Tx-M excretion was similarly reduced by aspirin and the combination of aspirin and nimesulide. In contrast, the combination of nimesulide and aspirin inhibited PGI-M excretion to a greater extent than aspirin (p = 0.001). Urinary 8-epi PGF(2alpha) excretion was elevated following PTCA compared with normal subjects (p = 0.002) and appeared to be unaffected by any of the treatments. CONCLUSIONS: The increase in TxA(2) during PTCA is primarily COX-1 dependent, and aspirin alone is effective in suppressing its formation. In contrast, prostacyclin generation is both COX-1 and COX-2 dependent. The inhibition of COX-1 and COX-2 did not prevent the production of 8-epi PGF(2alpha), suggesting that this is not enzymatically derived. The persistent generation of 8-epi PGF(2alpha) may contribute to the thrombosis and restenosis that complicate PTCA.