Ian Kerridge

Association between xenobiotic gene polymorphisms and non‐Hodgkin's lymphoma risk

Summary. The last four decades have seen a significant increase in the incidence of non‐Hodgkins lymphoma (NHL) as a possible result of increasing environmental carcinogen exposure, particularly pesticides and solvents. Based on the increasing evidence for an association between carcinogen exposure‐related cancer risk and xenobiotic gene polymorphisms, we have undertaken a case–control study of xenobiotic gene polymorphisms in individuals with a diagnosis of NHL. Polymorphisms of six xenobiotic genes (CYP1A1, GSTT1, GSTM1, PON1, NAT1, NAT2) were characterized in 169 individuals with NHL and 205 normal controls using polymerase chain reaction‐based methods. Polymorphic frequencies were compared using Fishers exact tests, and odds ratios for NHL risk were calculated. Among the NHL group, the incidence of GSTT1 null and PON1 BB genotypes were significantly increased compared with controls, 34%vs 14%, and 24%vs 11% respectively. Adjusted odds ratios calculated from multivariate analyses demonstrated that GSTT1 null conferred a fourfold increase in NHL risk (OR = 4·27; 95% CI, 2·40–7·61, P < 0·001) and PON1 BB a 2·9‐fold increase (OR = 2·92; 95% CI, 1·49–5·72, P = 0·002). Furthermore, GSTT1 null combined with PON1 BB or GSTM1 null conferred an additional risk of NHL. This is the first time that a PON1 gene polymorphism has been shown to be associated with cancer risk. We conclude that the two polymorphisms, GSTT1 null and PON1 BB, are common genetic traits that pose low individual risk but may be important determinants of overall population NHL risk, particularly among groups exposed to NHL‐related carcinogens.

Pre‐transplant cytomegalovirus (CMV) serostatus remains the most important determinant of CMV reactivation after allogeneic hematopoietic stem cell transplantation in the era of surveillance and preemptive therapy

B. George, N. Pati, N. Gilroy, M. Ratnamohan, G. Huang, I. Kerridge, M. Hertzberg, D. Gottlieb, K. Bradstock. Pre‐transplant cytomegalovirus (CMV) serostatus remains the most important determinant of CMV reactivation after allogeneic hematopoietic stem cell transplantation in the era of surveillance and preemptive therapy.
Transpl Infect Dis 2010: 12: 322–329. All rights reserved

Evidence, Ethics, and Values: A Framework for Health Promotion

We propose a new approach to guide health promotion practice. Health promotion should draw on 2 related systems of reasoning: an evidential system and an ethical system. Further, there are concepts, values, and procedures inherent in both health promotion evidence and ethics, and these should be made explicit. We illustrate our approach with the exemplar of intervention in weight, and use a specific mass-media campaign to show the real-world dangers of intervening with insufficient attention to ethics and evidence. Both researchers and health promotion practitioners should work to build the capacities required for evidential and ethical deliberation in the health promotion profession.

Methionine synthase genetic polymorphism MS A2756G alters susceptibility to follicular but not diffuse large B‐cell non‐Hodgkin's lymphoma or multiple myeloma

Summary. Lymphoproliferative diseases are characterized by chromosomal aberrations, and susceptibility may depend on inherited activity of enzymes required for DNA synthesis and methylation. We analysed genetic polymorphisms for methionine synthase (MS) A2756G, methylenetetrahydrofolate reductase (MTHFR) C677T and MTHFR A1298C in Caucasians with non‐Hodgkins lymphoma (NHL; n = 151), multiple myeloma (MM; n = 90) and 299 control subjects. The MS 2756 AG/GG genotypes were significantly under‐represented in NHL (26·2%) vs control subjects (37·2%; P = 0·02), and conferred a 2·4‐fold lower risk of follicular (odds ratio = 0·41, 95% confidence interval: 0·19–0·88, p = 0·02) but not diffuse large B‐cell lymphoma. MM patients showed no significant difference in the polymorphisms compared with control subjects.

Withdrawal and limitation of life-sustaining treatments in a paediatric intensive care unit and review of the literature

Objectives:  To examine withdrawal and limitation of life‐sustaining treatment (WLST) in an Australian paediatric intensive care unit (PICU) and to compare this experience with published data from other countries.

Selection of medical students according to their moral orientation

Introduction  Consideration has been given to the use of tests of moral reasoning in the selection procedure for medical students. We argue that moral orientation, rather than moral reasoning, might be more efficacious in minimising the likelihood of inappropriate ethical behaviour in medicine. A conceptualisation and measure of moral orientation are presented, together with findings from 11 samples of medical school applicants and students.

Specific Unwillingness to Donate Eyes: The Impact of Disfigurement, Knowledge and Procurement on Corneal Donation

Although willingness, attitudes and beliefs surrounding solid‐organ donation have been extensively investigated, much less is known about corneal donation. Despite evidence that a substantial number of families who agree to multiorgan donation also specifically refuse corneal donation, it is unclear why this occurs and what can be done to increase rates of corneal donation. We conducted a survey of 371 Australian adults regarding their views on corneal donation. Although willingness to donate corneas generally reflected a persons willingness to donate all of ones organs, unwillingness to donate corneas appeared to be due to other factors. Specifically, decisions not to donate appear to be driven by a range of concerns surrounding disfigurement. The survey also provides eye banks with reassurance about the acceptability of whole globe procurement, and recognition that research into blindness is a highly valued part of corneal donation. Finally, the survey identifies that many individuals see benefit in having their family engaged in the decision‐making process, suggesting that decisions about donation are more complex than a simple appeal to the autonomy of the deceased.

Community treatment orders in Australia: rates and patterns of use

Objectives: Community treatment orders (CTOs) allow clinicians to provide unconsented outpatient treatment to people living with mental illness. Though controversial and of uncertain efficacy, CTOs are used throughout Australia and internationally. We sought to determine the prevalence of CTO use in Australian states and territories, and to examine changes in the pattern of use over time. Method: Australian state and territory mental health review tribunals and health departments were surveyed for the most recent annual data on the total number of CTOs made and the total number of individual people placed on a CTO. Results: Rates of CTO use range from 30.2 per 100,000 population (in Tasmania) to 98.8 per 100,000 population (in Victoria). Use of CTOs in Australia is high by world standards, appears to be increasing over time, and varies significantly across jurisdictions. Conclusions: The high (by world standards), increasing and variable use of CTOs in Australia is concerning and raises important implications for mental health policymakers and legislators. Current mental health policy activity, particularly the new National Mental Health Commission, provides a unique opportunity to enhance transparency and accountability if regular and nationally uniform CTO data are collected and publically reported.

A Phase 1 study of the safety, pharmacokinetics and anti-leukemic activity of the anti-CD123 monoclonal antibody CSL360 in relapsed, refractory or high-risk acute myeloid leukemia

Abstract Acute myeloid leukemia (AML) blasts express high levels of interlekin-3 (IL-3) receptor-α (CD123). CSL360 is a recombinant, chimeric immunoglobulin G1 (IgG1), anti-CD123 monoclonal antibody (MoAb) that neutralizes IL-3 and demonstrates anti-leukemic activity in vitro. This phase 1 study assessed safety, pharmacokinetics and bioactivity of weekly intravenous CSL360 for 12 weeks in 40 patients with advanced AML across five dose levels (0.1–10.0 mg/kg). Other than mild infusion reactions, CSL360 was well tolerated. The maximal tolerated dose was not reached. The half-life was 4.9 days, and the area under the curve (AUC) and maximum concentration (Cmax) increased proportionally with dose. Doses ≥ 3.0 mg/kg resulted in complete saturation and down-regulation of CD123 and abolition of ex vivo proliferative responsiveness to IL-3, indicating adequate blockade of IL-3 signaling. Two patients responded, with one remaining in complete remission after 17 doses. CSL360 bound CD123 specifically, but did not induce anti-leukemic activity in most patients. While safe, MoAb blockade of CD123 function is insufficient as a therapeutic strategy.

From advance directives to advance care planning: current legal status, ethical rationales and a new research agenda

Abstract