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.     

Roxatidine versus ranitidine in the treatment of duodenal ulcers: A randomized double-blind controlled multicentre study in Singapore

Roxatidine acetate, a new H₂ receptor antagonist, was compared with ranitidine in the treatment of duodenal ulcers in a double-blind multicentre study. Eighty-four patients with endoscopically proven duodenal ulcer were randomized to receive 150 mg roxatidine acetate or 300 mg ranitidine at bedtime. Repeat endoscopy was performed after 4 weeks (25–33 days) and if the ulcer had not healed, another endoscopy was performed after a further 4 weeks of treatment. Using per protocol analysis 73.6% of ulcers treated with roxatidine healed at 4 weeks compared to 72.2% of ulcers treated with ranitidine (P=NS). The healing rates at 8 weeks were 92% with roxatidine and 83.3% with ranitidine (P=NS). Using equivalence tests, the healing rate of roxatidine was found to be equivalent to that of ranitidine within a 20% region. Roxatidine users took significantly less antacids than ranitidine users (P < 0.05). There were no significant adverse effects due to roxatidine or ranitidine. Roxatidine is a safe effective drug in the treatment of duodenal ulcers with a healing rate comparable to that of ranitidine.     

Scaffolding of antigen receptors for immunogenic versus tolerogenic signaling

Lymphocyte antigen receptors are responsible for inducing the opposite responses of immunity or tolerance. How the correct polarity of antigen receptor signaling is encoded has been an enduring enigma. Here we summarize recent advances defining key scaffolding molecules, CARMA1 (also known as CARD11) and the Cbl family of ubiquitin ligases, required for either immunogenic or tolerogenic signaling by antigen receptors. These scaffolding proteins may determine the polarity of response to antigen by promoting assembly around antigen receptors of competing multiprotein signal complexes: immunosomes versus tolerosomes. Each of the factors that influence immunogenicity or tolerogenicity--stage of lymphocyte differentiation, concurrent engagement of inhibitory or costimulatory receptors, extent of receptor crosslinking, and prior antigen experience--may be integrated in lymphocytes through their capacity to influence the probability of assembling immunosomes versus tolerosomes.     

Genome-wide ENU mutagenesis to reveal immune regulators

A complete list of molecular components for immune system function is now available with the completion of the human and mouse genome sequences. However, identification and functional annotation of genes involved in immunological processes require a discovery methodology that can efficiently and broadly analyze the complex interplay of these components in vivo. Our recent experience indicates that genome-wide chemical mutagenesis in the mouse is an extremely powerful methodology for the identification of genes required for complex immunological processes.     

Basic newborn care and neonatal resuscitation: a multi-country analysis of health system bottlenecks and potential solutions

Background

An estimated two-thirds of the world's 2.7 million newborn deaths could be prevented with quality care at birth and during the postnatal period. Basic Newborn Care (BNC) is part of the solution and includes hygienic birth and newborn care practices including cord care, thermal care, and early and exclusive breastfeeding. Timely provision of resuscitation if needed is also critical to newborn survival. This paper describes health system barriers to BNC and neonatal resuscitation and proposes solutions to scale up evidence-based strategies.

Methods

The maternal and newborn bottleneck analysis tool was applied by 12 countries in Africa and Asia as part of the Every Newborn Action Plan process. Country workshops engaged technical experts to complete the survey tool, which is designed to synthesise and grade health system "bottlenecks" that hinder the scale up of maternal-newborn intervention packages. We used quantitative and qualitative methods to analyse the bottleneck data, combined with literature review, to present priority bottlenecks and actions relevant to different health system building blocks for BNC and neonatal resuscitation.

Results

Eleven of the 12 countries provided grading data. Overall, bottlenecks were graded more severely for resuscitation. The most severely graded bottlenecks for BNC were health workforce (8 of 11 countries), health financing (9 out of 11) and service delivery (7 out of 9); and for neonatal resuscitation, workforce (9 out of 10), essential commodities (9 out of 10) and service delivery (8 out of 10). Country teams from Africa graded bottlenecks overall more severely. Improving workforce performance, availability of essential commodities, and well-integrated health service delivery were the key solutions proposed.

Conclusions

BNC was perceived to have the least health system challenges among the seven maternal and newborn intervention packages assessed. Although neonatal resuscitation bottlenecks were graded more severe than for BNC, similarities particularly in the workforce and service delivery building blocks highlight the inextricable link between the two interventions and the need to equip birth attendants with requisite skills and commodities to assess and care for every newborn. Solutions highlighted by country teams include ensuring more investment to improve workforce performance and distribution, especially numbers of skilled birth attendants, incentives for placement in challenging settings, and skills-based training particularly for neonatal resuscitation.