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.

The neuro-immune pathophysiology of central and peripheral fatigue in systemic immune-inflammatory and neuro-immune diseases

Many patients with systemic immune-inflammatory and neuro-inflammatory disorders, including depression, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's disease, cancer, cardiovascular disorder, Parkinson's disease, multiple sclerosis, stroke, and chronic fatigue syndrome/myalgic encephalomyelitis, endure pathological levels of fatigue. The aim of this narrative review is to delineate the wide array of pathways that may underpin the incapacitating fatigue occurring in systemic and neuro-inflammatory disorders. A wide array of immune, inflammatory, oxidative and nitrosative stress (O&NS), bioenergetic, and neurophysiological abnormalities are involved in the etiopathology of these disease states and may underpin the incapacitating fatigue that accompanies these disorders. This range of abnormalities comprises: increased levels of pro-inflammatory cytokines, e.g., interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF) α and interferon (IFN) α; O&NS-induced muscle fatigue; activation of the Toll-Like Receptor Cycle through pathogen-associated (PAMPs) and damage-associated (DAMPs) molecular patterns, including heat shock proteins; altered glutaminergic and dopaminergic neurotransmission; mitochondrial dysfunctions; and O&NS-induced defects in the sodium-potassium pump. Fatigue is also associated with altered activities in specific brain regions and muscle pathology, such as reductions in maximum voluntary muscle force, downregulation of the mitochondrial biogenesis master gene peroxisome proliferator-activated receptor gamma coactivator 1-alpha, a shift to glycolysis and buildup of toxic metabolites within myocytes. As such, both mental and physical fatigue, which frequently accompany immune-inflammatory and neuro-inflammatory disorders, are the consequence of interactions between multiple systemic and central pathways.

Protein kinase C isozymes as potential therapeutic targets in immune disorders

Background: Members of the protein kinase C (PKC) family are key signalling mediators in immune responses, and pharmacological inhibition of PKCs may be useful for treating immune-mediated diseases. Objective: To review and discuss the insights gained so far into various PKC isozymes and the therapeutic potential and challenges of developing PKC inhibitors for immune disorder therapy. Methods: A literature review of the role of PKCs in immune cell signalling and recent studies describing immune functions associated with PKC isozyme deficiency in relevant mouse disease models, followed by specific case studies of current and potential therapeutic strategies targeting PKCs. Results/conclusion: There is vast amount of data supporting PKC isozymes as attractive drug targets for certain immune disorders. Although the development of specific PKC isozyme inhibitors has been challenging, some progress has been made. It remains to be seen if broad-scale or isozyme-selective inhibition of PKC will have clinical efficacy.

Depression's multiple comorbidities explained by (neuro)inflammatory and oxidative & nitrosative stress pathways

There is now evidence that depression, as characterized by melancholic symptoms, anxiety, and fatigue and somatic (F&S) symptoms, is the clinical expression of peripheral cell-mediated activation, inflammation and induction of oxidative and nitrosative stress (IO&NS) pathways and of central microglial activation, decreased neurogenesis and increased apoptosis. This review gives an explanation for the multiple “co-morbidities” between depression and a large variety of a) brain disorders related to neurodegeneration, e.g. Alzheimer’s, Parkinson’s and Huntington’s disease, multiple sclerosis and stroke; b) medical disorders, such as cardiovascular disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, inflammatory bowel disease, irritable bowel syndrome, leaky gut, diabetes type 1 and 2, obesity and the metabolic syndrome, and HIV infection; and c) conditions, such as hemodialysis, interferon-α-based immunotherapy, the postnatal period and psychosocial stressors. The common denominator of all those disorders/conditions is the presence of microglial activation and/or activation of peripheral IO&NS pathways. There is evidence that shared peripheral and / or central IO&NS pathways underpin the pathophysiology of depression and the previously mentioned disorders and that activation of these IO&NS pathways contributes to shared risk. The IO&NS pathways function as a smoke sensor that detect threats in the peripheral and central parts of the body and signal these threats as melancholic, anxiety, and fatigue and somatic (F&S) symptoms. The presence of concomitant depression is strongly associated with a lower quality of life and increased morbidity and mortality in medical disorders. This may be explained since depression contributes to increased (neuro)inflammatory burden and may therefore drive the inflammatory and degenerative progression. It is concluded that the activation of peripheral and / or central IO&NS pathways may explain the co-occurrence of depression with the above disorders. This shows that depression belongs to the spectrum of inflammatory and degenerative disorders.

The global burden of musculoskeletal conditions for 2010: an overview of methods.

The objective of this paper is to provide an overview of methods used for estimating the burden from musculoskeletal (MSK) conditions in the Global Burden of Diseases 2010 study. It should be read in conjunction with the disease-specific MSK papers published in Annals of Rheumatic Diseases. Burden estimates (disability-adjusted life years (DALYs)) were made for five specific MSK conditions: hip and/or knee osteoarthritis (OA), low back pain (LBP), rheumatoid arthritis (RA), gout and neck pain, and an 'other MSK conditions' category. For each condition, the main disabling sequelae were identified and disability weights (DW) were derived based on short lay descriptions. Mortality (years of life lost (YLLs)) was estimated for RA and the rest category of 'other MSK', which includes a wide range of conditions such as systemic lupus erythematosus, other autoimmune diseases and osteomyelitis. A series of systematic reviews were conducted to determine the prevalence, incidence, remission, duration and mortality risk of each condition. A Bayesian meta-regression method was used to pool available data and to predict prevalence values for regions with no or scarce data. The DWs were applied to prevalence values for 1990, 2005 and 2010 to derive years lived with disability. These were added to YLLs to quantify overall burden (DALYs) for each condition. To estimate the burden of MSK disease arising from risk factors, population attributable fractions were determined for bone mineral density as a risk factor for fractures, the occupational risk of LBP and elevated body mass index as a risk factor for LBP and OA. Burden of Disease studies provide pivotal guidance for governments when determining health priority areas and allocating resources. Rigorous methods were used to derive the increasing global burden of MSK conditions.

Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses

The genesis of severe fatigue and disability in people following acute pathogen invasion involves the activation of Toll-like receptors followed by the upregulation of proinflammatory cytokines and the activation of microglia and astrocytes. Many patients suffering from neuroinflammatory and autoimmune diseases, such as multiple sclerosis, Parkinson's disease and systemic lupus erythematosus, also commonly suffer from severe disabling fatigue. Such patients also present with chronic peripheral immune activation and systemic inflammation in the guise of elevated proinflammtory cytokines, oxidative stress and activated Toll-like receptors. This is also true of many patients presenting with severe, apparently idiopathic, fatigue accompanied by profound levels of physical and cognitive disability often afforded the non-specific diagnosis of chronic fatigue syndrome.

Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut–brain pathways

The nature of depression has recently been reconceptualized, being conceived as the clinical expression of activated immune-inflammatory, oxidative, and nitrosative stress (IO&NS) pathways, including tryptophan catabolite (TRYCAT), autoimmune, and gut–brain pathways. IO&NS pathways are similarly integral to the pathogenesis of inflammatory bowel disease (IBD). The increased depression prevalence in IBD associates with a lower quality of life and increased morbidity in IBD, highlighting the role of depression in modulating the pathophysiology of IBD.This review covers data within such a wider conceptualization that better explains the heightened co-occurrence of IBD and depression. Common IO&NS underpinning between both disorders is evidenced by increased pro-inflammatory cytokine levels, eg, interleukin-1 (IL-1) and tumor necrosis factor-α, IL-6 trans-signalling; Th-1- and Th-17-like responses; neopterin and soluble IL-2 receptor levels; positive acute phase reactants (haptoglobin and C-reactive protein); lowered levels of negative acute phase reactants (albumin, transferrin, zinc) and anti-inflammatory cytokines (IL-10 and transforming growth factor-β); increased O&NS with damage to lipids, proteinsm and DNA; increased production of nitric oxide (NO) and inducible NO synthase; lowered plasma tryptophan but increased TRYCAT levels; autoimmune responses; and increased bacterial translocation. As such, heightened IO&NS processes in depression overlap with the biological underpinnings of IBD, potentially explaining their increased co-occurrence. This supports the perspective that there is a spectrum of IO&NS disorders that includes depression, both as an emergent comorbidity and as a contributor to IO&NS processes. Such a frame of reference has treatment implications for IBD when “comorbid” with depression.

Comparison of brood size and juvenile weight between a blue strain and normal-coloured strains of the Australian freshwater crayfish Cherax Destructor Clark (Decapoda: Parastacidae)

A blue strain of the yabby Cherax destructor albidus was compared to two normal-coloured strains of C. d. destructor and C. d. albidus for brood size and juvenile weight. Reproductive performance of the blue strain was found to be significantly poorer than the two normal-coloured strains. Similarly, the weight of newly independent juveniles was also found to be significantly lower for the blue strain. No differences were detected between the two normal-coloured strains in either reproductive performance or size of newly independent juveniles. The phenotypic differences between the blue strain and normal-coloured strains are most likely genetic. However, further studies are needed to investigate whether these differences are due to pleiotropy or inbreeding effects.

Performance of juvenile Murray cod, Maccullochella peelii peelii (Mitchell), fed with diets of different protein to energy ratio

The results of a 56-day experiment on juvenile Murray cod, Maccullochella peelii peelii, an Australian native fish with a high aquaculture potential, of mean weight 14.9 ± 0.04 g, fed with five experimental diets, one a series of 40% protein content and lipid levels of 10, 17 and 24% (P40L10, P40L17 and P40L24), and another of 50% protein and 17 and 24% (P50L17 and P50L24) lipid are presented. The specific growth rate (SGR) (% day−1) of fish maintained on different diets ranged from 1.18 to 1.41, and was not significantly different between dietary treatments, except P40L10 and the rest. However, there was a general tendency for SGR to increase with increasing dietary lipid content at both protein levels. The food conversion ratio (FCR) for the 40% protein series diets were poorer compared with those of the 50% protein diets, and the best FCR of 1.14 was observed with the P50L17 diet. The protein efficiency ratio (PER), however, was better in fish reared on low protein diets. The net protein utilization (NPU) also did not differ significantly (P > 0.05) in relation to dietary treatment. As in the case of PER the highest NPU was observed in Murray cod reared on diet P40L24 and the lowest in fish fed with diet P50L24. The carcass lipid content reflected that of the diets, when significant increases in the lipid content was observed in relation to dietary lipid content at both protein levels. However, body muscle lipid content did not increase with increasing dietary lipid content, and was significantly lower than in the whole body. The fatty acids found in highest concentration amongst the saturates, monoenes and polyunsaturates (PUFAs) were 16 : 0, 18 : 1n-9 and 22 : 6n-3, respectively, and each of these accounted for more than 60% of each of the group's total. The muscle fatty acid content was affected by the dietary lipid content; for example the total amount (in μg mg−1 lipid) of monoenes ranged from 72 ± 5.1 (P40L10) to 112 ± 10 (P40L24) and 112 ± 2.8 (P50L17) to 132 ± 11.8 (P50L24) and the n-6 series fatty acids increased with increasing dietary lipid content, although not always significant. Most notably, 18 : 2n-6 increased with the dietary lipid level in both series of diets.

Preliminary study on the use of synthetic substrate for juvenile stage production of the yabby, Cherax destructor (Clark) (Decapoda: Parastacidae)

Juvenile Cherax destructor (commonly called the yabby) (mean weight 48.3 mg) were cultured intensively (stocking density 360/m²) under controlled conditions for 48 days. The animals were provided with a combination of food (high protein pellets and/or natural feed organisms attached to a conditioned synthetic substrate) and refuge. Fastest growth and highest yield was recorded when both pellets and the conditioned synthetic material were provided. Although the yabbies sheltered in the synthetic substrate, it did not increase survival. Juvenile yabbies (< 200 mg) were able to graze on small organisms attached to the synthetic material but this ability appeared to decline as the yabbies grew to a larger size. The use of artificial substrates in the intensive nursery phase production of juvenile freshwater crayfish is discussed.

Voluntarism, salvation, and rescue : British juvenile migration to Australia and Canada, 1890-1939

This article explores the relationships between governments and selected voluntary organisations involved in British migration to Australia and Canada from the 1890s to the Second World War. Prior to the Great War, there was considerable ill feeling by Dominion governments, especially Australian, towards philanthropic organisations, which appeared to undermine official immigration schemes through their attempts to reclaim and transplant the unwanted. Although voluntary associations were later subsidised by the British government and came under the group nomination schemes of the 1922 Empire Settlement Act, they were still viewed with suspicion. Organisations focusing on 'salvation', 'redemption' and 'rescue' in their migration work, however, provide us with an alternative ideology to the idea of building up 'fit populations' in the Dominions, where the notion of 'fitness' was perceived in a number of ways, not least in terms of class.

Growth performance, feed efficiency and fatty acid composition of juvenile Murray cod, Maccullochella peelii peelii, fed graded levels of canola and linseed oil

n two independent experiments, the effects of dietary inclusion of canola and linseed oil were evaluated in juvenile Murray cod (Maccullochella peelii peelii, Mitchell) over a 112-day period. In each experiment, fish received one of five semi-purified diets in which the dietary fish oil was replaced with canola oil (Experiment A) or linseed oil (Experiment B) in graded increments of 25% (0–100%). Murray cod receiving the graded canola and linseed oil diets ranged in final weight from 112.7 ± 7.6 to 73.8 ± 9.9 g and 93.9 ± 3.6 to 74.6 ± 2.2 g, respectively, and exhibited a negative trend in growth as the inclusion level increased. The fatty acid composition of the fillet and liver were modified extensively to reflect the fatty acid composition of the respective diets. Levels of oleic acid (18:1 n-9) and linoleic acid (18:2 n-6) increased with each level of canola oil inclusion while levels of α-linolenic acid (18:3 n-3) increased with each level of linseed oil inclusion. The concentration of n-3 highly unsaturated fatty acids in the fillet and liver decreased as the amount of vegetable oil in the diets increased. It is shown that the replacement of fish oil with vegetable oils in low fish meal diets for Murray cod is possible to a limited extent. Moreover, this study reaffirms the suggestion for the need to conduct ingredient substitution studies for longer periods and where possible to base the conclusions on regression analysis in addition to anova.

Dispersal and recruitment of juvenile Red-capped Robins, Petroica goodenovii

Data on the dispersal and recruitment of juvenile birds following fledging are largely unreported for Australian birds. In this study, we investigated the short-distance dispersal of a sample of colour-banded, juvenile Red-capped Robins, Petroica goodenovii, in Terrick Terrick National Park, Victoria, Australia. Of 67 colour-banded juvenile birds that successfully reached independence during the 2000–01 breeding season, eight were recruited into the study area or adjacent areas for the following breeding season. A ninth bird was resighted in Gunbower State Forest, 36 km from where it was banded. This is the furthest recorded dispersal movement of a Red-capped Robin. Of 59 colour-banded juvenile birds that reached independence during the 2001–02 season, four remained within the study area for the remainder of the breeding season, but these birds were not present in the study area during the following breeding season. Juvenile birds that successfully reached independence and dispersed were heavier as nestlings, when controlled for age and date, than birds that disappeared (assumed dead) before reaching independence. Estimates of Red-capped Robin abundances within Terrick Terrick National Park were greater than those of nearby eucalypt woodlands, suggesting that the White Cypress-pine, Callitris glaucophylla, woodlands within the park offer good-quality habitat for Red-capped Robins and may be saturated with breeding territories. Thus, juveniles may be forced to establish breeding territories far from their natal territories. These results are discussed in relation to avenues for further research on juvenile dispersal in Australian birds and their conservation implications.

What`s the story? An exploration of narrative language abilities in male juvenile offenders

This paper is concerned with the narrative language (story telling) abilities of a group of juvenile offenders completing community-based court orders in Melbourne, Australia. A convenience sample of 30 male young offenders was compared with 50 male non-offenders attending government high schools in the same region of Melbourne. Participants provided an audiotaped description of a six-frame cartoon (the “Flowerpot Incident”). Samples were transcribed and subjected to story grammar analysis, to examine differences between groups regarding both structural and qualitative adequacy. Young offenders produced narratives which were significantly poorer than those of controls with respect to the presence and adequacy of the seven story grammar elements described by Stein and Glenn (In R. O. Freedle (Ed.), New Directions in Discourse Processing (pp. 53-120) 1979). Findings are discussed in relation to implications for investigative and evidentiary interviewing.