Relationship of glutathione S-transferase genotypes with side-effects of pulsed cyclophsphamide therapy in patients with systemic lupus erythematosus

Aims
Cyclophosphamide (CTX) is an established treatment of severe systemic lupus erythematosus (SLE). Cytotoxic CTX metabolites are mainly detoxified by multiple glutathione S-transferases (GSTs). However, data are lacking on the relationship between the short-term side-effects of CTX therapy and GST genotypes. In the present study, the effects of common GSTM1, GSTT1, and GSTP1 genetic mutations on the severity of myelosuppression, gastrointestinal (GI) toxicity, and infection incidences induced by pulsed CTX therapy were evaluated in patients SLE.
Methods
DNA was extracted from peripheral leucocytes in patients with confirmed SLE diagnosis (n = 102). GSTM1 and GSTT1 null mutations were analyzed by a polymerase chain reaction (PCR)-multiplex procedure, whereas the GSTP1 codon 105 polymorphism (Ile→Val) was analyzed by a PCR-restriction fragment length polymorphism (RFLP) assay.
Results
Our study demonstrated that SLE patients carrying the genotypes with GSTP1 codon 105 mutation [GSTP1*-105I/V (heterozygote) and GSTP1*-105 V/V (homozygote)] had an increased risk of myelotoxicity when treated with pulsed high-dose CTX therapy (Odds ratio (OR) 5.00, 95% confidence interval (CI) 1.96, 12.76); especially in patients younger than 30 years (OR 7.50, 95% CI 2.14, 26.24), or in patients treated with a total CTX dose greater than 1.0 g (OR 12.88, 95% CI 3.16, 52.57). Similarly, patients with these genotypes (GSTP1*I/V and GSTP1*V/V) also had an increased risk of GI toxicity when treated with an initial pulsed high-dose CTX regimen (OR 3.33, 95% CI 1.03, 10.79). However, GSTM1 and GSTT1 null mutations did not significantly alter the risks of these short-term side-effects of pulsed high-dose CTX therapy in SLE patients.
Conclusions
The GSTP1 codon 105 polymorphism, but not GSTM1 or GSTT1 null mutations, significantly increased the risks of short-term side-effects of pulsed high-dose CTX therapy in SLE patients. Because of the lack of selective substrates for a GST enzyme phenotyping study, timely detection of this mutation on codon 105 may assist in optimizing pulsed high-dose CTX therapy in SLE patients.

Use of in vitro critical inhibitory concentration, a novel approach to predict in vivo synergistic bactericidal effect of combined amikacin and piperacillin against pseudomonas aeruginosa in a systemic rat infection model

PURPOSE: This study was undertaken to explore the use of in vitro critical inhibitory concentration (CIC) as a surrogate marker relating the pharmacokinetic (PK) parameters to in vivo bactericidal synergistic effect [pharmacodynamic (PD)] of amikacin + piperacillin combination against Pseudomonas aeruginosa in a systemic rat infection model. METHODS: The in vitro antibacterial activities of amikacin and piperacillin, alone and in combinations at various ratios of the concentrations, were tested against a standard [5 x 10(5) colony-forming units (CFU)/ml] and a large (1.5 x 10(8) CFU/ml) inoculum of P. aeruginosa ATCC 9027 using a modified survival-time method. The CIC of each individual antibiotic for the different combinations was determined using a cup-plate method. In vivo studies were performed on Sprague-Dawley rats using a systemic model of infection with P. aeruginosa ATCC 9027. PK profiles and in vivo killing effects of the combination at different dosing ratios were studied. RESULTS: An inoculum effect was observed with the antibiotics studied. Synergy was seen against both the inocula at the following concentration ratios: 70% C(ami) + 30% C(pip) and 75% C(ami) + 25% C(pip), where C(ami) and C(pip) are the concentrations of amikacin and piperacillin to produce a 1000-fold decrease in bacterial population over 5 h, respectively. The CIC values determined corroborated with the order of in vitro bacterial killing observed for the antibiotic combinations. The dosing ratio of 12.6 mg/kg amikacin + 36 mg/kg piperacillin (a 70:30 ratio of the individual doses) exhibited the greatest killing in vivo when compared to the other ratios. The PK-PD relationships were described by simple, linear regression equations using the area under the in vivo killing curve as a PD marker and the AUCIC(ami)/CIC(ami) + AUCIC(pip)/CIC(pip), AUC(ami)/CIC(ami) + AUC(pip)/CIC(pip), C(max,ami)/CIC(ami) + C(max,pip)/CIC(pip), and AUCIC(ami)/MIC(ami) + AUCIC(pip)/MIC(pip) as PK markers for the amikacin + piperacillin combination. CONCLUSION: The combination of amikacin and piperacillin exhibited synergistic killing effect on P. aeruginosa that could be modeled using CIC as a surrogate marker relating the PK parameters to in vivo bactericidal effect.

A systemic approach to the database marketing process

The role of database marketing (DBM) has become increasingly important for organisations that have large databases of information on customers with whom they deal directly. At the same time, DBM models used in practice have increased in sophistication. This paper examines a systemic view of DBM and the role of analytical techniques within DBM. It extends existing process models to develop a systemic model that encompasses the increased complexity of DBM in practice. The systemic model provides a framework to integrate data mining, experimental design and prioritisation decisions. This paper goes on to identify opportunities for research in DBM, including DBM process models used in practice, the use of evolutionary operations techniques in DBM, prioritisation decisions, and the factors that surround the uptake of DBM.

A model to enable organisational cultural change using systemic strategic human resource management

Cultural change in organisations is both difficult to implement and hard to achieve. In this paper, theory from strategic human resource management, organisational cultural change, systemic thinking and practice, and punctuated equilibrium, is integrated in order to build a model for organisational culture change. Evidence is provided showing the capacity of the model to enable researchers and organisational change agents to improve the success of organisational cultural change programs.

Interpersonal trust and formal controls in low systemic trust societies

This study is concerned with the role of interpersonal trust in management control. On the basis of a questionnaire survey and interviews of senior managers from business organisations in sri lanka, the study explores the control behaviour of superior managers when they trust or distrust their subordinates. Sri lanka, a society in which the dependence on interpersonal trust is high, was chosen for the study to maximise the effect of interpersonal trust.

The findings of this study indicate that a superior's high trust in a subordinate is associated with a low level of monitoring, a high level of social interactions, and a low reliance on formal controls. In contrast, a superior's low level of trust in a subordinate is associated with a high level of monitoring, a low level of social interactions, and a high reliance on formal controls. Because the data emanate from experienced senior managers, these findings are at least indicative of control behaviour of superior managers in sri lanka and possibly of similar countries in asia. An understanding of the control behaviour of managers in this region is particularly important for designing and implementing effective controls systems for firms, subsidiaries, branches or joint-ventures operating in the region.

Mother–infant psychotherapy and perinatal psychiatry: current clinical practice and future directions

Objective: To explore trends in the practice of mother-infant psychotherapy among perinatal psychiatry clinicians based in Melbourne.Methods: A cross-sectional survey with a purpose designed self-report questionnaire was used to assess the attitudes and practices of 47 perinatal and infant psychiatry clinicians in their use and understanding of mother-infant psychotherapy.Results: Seventy per cent of clinicians in this field of psychotherapy who responded to the questionnaire subscribe to a psychodynamic model, although cognitive behavioural models are also used. The interventions were mostly used in conjunction with other interventions, would be more accurately described as 'parent-infant psychotherapy', and non-psychiatrists in the area tended to be more likely to be formally trained in psychotherapy, but only 4% were formally trained in specific mother-infant psychotherapy. There was a unanimous request for further clinical training in this area.Conclusions: The emerging field of perinatal psychiatry needs to develop coherent therapeutic models and conduct outcome trials on specific interventions. Specific trainings in these models, in assessment and in diagnostic frameworks are required to enhance clinical efficacy, for research and service development purposes.

Short-term psychodynamic psychotherapy: review of recent process and outcome studies

Short-term psychodynamic psychotherapy (STPP) is a widely practised form of psychological intervention. Given that the Roth and Fonagy (1996) review concluded that there was a lack of confirming evidence for STPP, the current review is focused on studies published between 1996 and 2006 that evaluate the efficacy of STPP. As a result of a systematic literature review, 18 studies were found that met inclusion criteria consistent with those used by Roth and Fonagy (1996) for selection of studies, patient groupings and definition of therapeutic method. In general these studies add to an increasing body of evidence suggesting that STPP can be an effective psychological treatment for individuals experiencing mental health problems. Specifically, for depression STPP can be equal in effects to other psychological treatments and is significantly better than no treatment in the short term. Furthermore, emerging process data indicate that there is a significant relationship between the use of specific psychodynamic therapeutic techniques and the alleviation of depressive symptoms. Increasing evidence has emerged to support STPP as a treatment for generalized anxiety disorder, panic disorder and some personality disorders. There remains limited evidence for the use of STPP treatment for patients with anxiety disorders that relate more to stress. Very limited and inconclusive evidence currently exists to support STPP as a treatment for bipolar disorder, eating disorders and drug dependency. Future research needs to include broader assessment measures, long-term follow up, studies that maintain an identifiable focus, and research that includes a focus on psychotherapy process variables as they interact with outcomes.

Systemic activation of dendritic cells by toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity

The mechanisms responsible for the immunosuppression associated with sepsis or some chronic blood infections remain poorly understood. Here we show that infection with a malaria parasite (Plasmodium berghei) or simple systemic exposure to bacterial or viral Toll-like receptor ligands inhibited cross-priming. Reduced cross-priming was a consequence of downregulation of cross-presentation by activated dendritic cells due to systemic activation that did not otherwise globally inhibit T cell proliferation. Although activated dendritic cells retained their capacity to present viral antigens via the endogenous major histocompatibility complex class I processing pathway, antiviral responses were greatly impaired in mice exposed to Toll-like receptor ligands. This is consistent with a key function for cross-presentation in antiviral immunity and helps explain the immunosuppressive effects of systemic infection. Moreover, inhibition of cross-presentation was overcome by injection of dendritic cells bearing antigen, which provides a new strategy for generating immunity during immunosuppressive blood infections.

Isoflavones from red clover improve systemic arterial compliance but not plasma lipids in menopausal women

The possibility that the heightened cardiovascular risk associated with the menopause can be reduced by increasing dietary isoflavone intake was tested in 17 women by measuring arterial compliance, an index of the elasticity of large arteries such as the thoracic aorta. Compliance diminishes with age and menopause. An initial 3- to 4-week run-in period and a 5-week placebo period were followed by two 5-week periods of active treatment with 40 mg and then 80 mg isoflavones derived from red clover containing genistein, daidzein, biochanin, and formononetin in 14 and 13 women, respectively, with 3 others serving as placebo controls throughout. Arterial compliance, measured by ultrasound as a pressure (carotid artery) and volume (outflow into aorta) relationship, was determined after each period; plasma lipids were measured twice during each period. Urinary output of isoflavones was also determined. Arterial compliance rose by 23% relative to that during the placebo period with the 80-mg isoflavone dose and slightly less with the 40-mg dose (mean6SEM: placebo, 19.761.5; 40 mg, 23.760.7; 80 mg, 24.46 1.4). In the three women receiving continuous placebo, compliance was 16 6 2.2, similar to that during the run-in period for the remaining subjects (17 6 2.1). ANOVA showed a significant (P 5 , 0.001) difference between treatments; by Bonferroni multiple comparisons and by paired t test, differences were significant between placebo and 40- and 80-mg isoflavone doses (by paired t test: P50.039 for placebo vs. 40 mg; P 5 0.018 for placebo vs. 80 mg). Plasma lipids were not significantly affected. An important cardiovascular risk factor, arterial compliance, which diminishes with menopause, was significantly improved with red clover isoflavones. As diminished compliance leads to systolic hypertension and may increase left ventricular work, the findings indicate a potential new therapeutic approach for improved cardiovascular function after menopause.

Soy isoflavones improve systemic arterial compliance but not plasma lipids in menopausal and perimenopausal women

The possibility that the heightened cardiovascular risk associated with the menopause, which is said to be ameliorated by soybeans, can be reduced with soy isoflavones was tested in 21 women. Although several were perimenopausal, all have been included. A placebo-controlled crossover trial tested the effects of 80-mg daily isoflavones (45 mg genistein) over 5- to 10-week periods. Systemic arterial compliance (arterial elasticity), which declined with age in this group, improved 26% (P < .001) compared with placebo. Arterial pressure and plasma lipids were unaffected. The vasodilatory capacity of the microcirculation was measured in nine women; high acetylcholine-mediated dilation in the forearm vasculature was similar with active and placebo treatments. LDL oxidizability measured in vitro was unchanged. Thus, one important measure of arterial health, systemic arterial compliance, was significantly improved in perimenopausal and menopausal women taking soy isoflavones to about the same extent as is achieved with conventional hormone replacement therapy.