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.

Top predators as biodiversity regulators : the dingo Canis lupus dingo as a case study

Top-order predators often have positive effects on biological diversity owing to their key functional roles in regulating trophic cascades and other ecological processes. Their loss has been identified as a major factor contributing to the decline of biodiversity in both aquatic and terrestrial systems. Consequently, restoring and maintaining the ecological function of top predators is a critical global imperative. Here we review studies of the ecological effects of the dingo Canis lupus dingo, Australia's largest land predator, using this as a case study to explore the influence of a top predator on biodiversity at a continental scale. The dingo was introduced to Australia by people at least 3500 years ago and has an ambiguous status owing to its brief history on the continent, its adverse impacts on livestock production and its role as an ecosystem architect. A large body of research now indicates that dingoes regulate ecological cascades, particularly in arid Australia, and that the removal of dingoes results in an increase in the abundances and impacts of herbivores and invasive mesopredators, most notably the red fox Vulpes vulpes. The loss of dingoes has been linked to widespread losses of small and medium-sized native mammals, the depletion of plant biomass due to the effects of irrupting herbivore populations and increased predation rates by red foxes. We outline a suite of conceptual models to describe the effects of dingoes on vertebrate populations across different Australian environments. Finally, we discuss key issues that require consideration or warrant research before the ecological effects of dingoes can be incorporated formally into biodiversity conservation programs.

Venous thromboembolism and underutilisation of anticoagulant thromboprophylaxis in hospitalised patients with inflammatory bowel disease

Background: Venous thromboembolism (VTE) is a well-recognised extra-intestinal manifestation of inflammatory bowel disease (IBD). Despite the widespread support for anticoagulant prophylaxis in hospitalised IBD patients, the utilisation and efficacy in clinical practice are unknown. Aims: The aim of this study was to assess the prevalence and clinical features of VTE among hospitalised IBD patients and ascertain whether appropriate thromboprophylaxis had been administered. Methods: All patients with a discharge diagnosis of Crohn disease or ulcerative colitis and VTE were retrospectively identified using International Classification of Diseases, tenth revision codes from medical records at our institution from July 1998 to December 2009. Medical records were then reviewed for clinical history and utilisation of thromboprophylaxis. Statistical analysis was performed by Mann-Whitney test and either χ2 tests or Fisher's exact tests. Results: Twenty-nine of 3758 (0.8%) IBD admissions suffered VTE, 13 preadmission and 16 during admission. Of these 29 admissions (in 25 patients), 24% required intensive care unit and 10% died. Of the 16 venous thrombotic events that occurred during an admission, eight (50%) did not receive anticoagulant thromboprophylaxis and eight (50%) occurred despite thromboprophylaxis. Most thromboembolism despite prophylaxis occurred post-intestinal resection (n = 5, 63%). Conclusion: Thromboprophylaxis is underutilised in half of IBD patients suffering VTE. Prescription of thromboprophylaxis for all hospitalised IBD patients, including dual pharmacological and mechanical prophylaxis in postoperative patients, may lead to a reduction in this preventable complication of IBD. © 2014 Royal Australasian College of Physicians.

Adding a new anticoagulant or antiplatelet agent for patient receiving aspirin after an acute coronary syndrome? - Results from a pairwise and network meta-analysis of randomized-controlled trials

 Objectives: To synthesize the efficacy and safety outcomes from randomized-controlled trials (RCTs) regarding new oral anticoagulant, protease-activated receptor-1 (PAR-1) antagonist, and warfarin adjunctive to aspirin for patients after acute coronary syndrome (ACS) via pair-wise and network meta-analyses.
Methods: A comprehensive literature search was performed in Embase, Medline, Cochrane Library Web of Knowledge, and Scopus. The pair-wise meta-analysis was undertaken respectively to each agent/treatment category via Revmen 5.1. In order to estimate the relative efficacy of each agent/treatment category whilst preserving the randomized comparisons within each trial, a Bayesian network meta-analysis was conducted in WinBUGS using both fixed- and random-effects model. Covariate analysis was performed to explore the effects of length of follow-up and age of subject on the final results.
Results: In total, 23 RCTs were included in the meta-analysis. As shown by the results (OR,95%CI) for the pair-wise meta-analysis, new oral anticoagulants (0.85, [0.78, 0.93] and 3.04, [2.21, 4.19]), PAR-1 antagonists (0.80, [0.52, 1.22] and 1.55, [1.25, 1.93]) and warfarin (0.87, [0.74, 1.02] and 1.77, [1.46, 2.14]) might be able to provide better outcome in the incidences of major adverse events (MAE) but with higher bleeding risk comparing to aspirin treatment alone. Based on the model fit assessment, the random-effects model was adopted. The network meta-analysis (treatment effect comparing to aspirin lone) identified ximelagatran (-0.3044, [-0.8601, 0.2502]), dabigatran (-0.2144, [-0.8666, 0.4525]), rivoroxaban (-0.2179, [-0.5986, 0.1628]) and vorapaxar (-0.2272, [-0.81, 0.1664]) produced better improvements in MAE incidences whereas vorapaxar (0.3764, [-0.4444, 1.124]), warfarin (0.663, [0.3375, 1.037]), ximelagatran (0.7509, [-0.4164, 2.002]) and apixaban (0.8594, [-0.0049, 1.7]) produced less major bleeding events. The indirect comparisons among drug category (difference in incidence comparing to aspirin lone) showed new oral anticoagulants (-0.1974, [-0.284, -0.111]) and PAR-1 antagonists (-0.1239, [-0.215, -0.033]) to besuperior to warfarin (-0.1004, [-0.166, -0.035]) in the occurrences of MAE whereas PAR-1 antagonists (0.4292, [0.2123, 0.6476]) afforded better outcomes in major bleeding events against warfarin (0.5742, [0.3889, 0.7619]) and new oral anticoagulants (1.169, [0.8667, 1.485]).
Conclusion: Based on the study results, we cannot recommend the routine administration of new oral anticoagulant as add-on treatment for patients after ACS. However, for ACS patients comorbid with atrial fibrillation, new oral anticoagulant might be superior to warfarin in both efficacy and safety outcomes.

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.

More than mere numbers: the impact of lethal control on the social stability of a top-order predator

Population control of socially complex species may have profound ecological implications that remain largely invisible if only their abundance is considered. Here we discuss the effects of control on a socially complex top-order predator, the dingo (Canis lupus dingo). Since European occupation of Australia, dingoes have been controlled over much of the continent. Our aim was to investigate the effects of control on their abundance and social stability. We hypothesized that dingo abundance and social stability are not linearly related, and proposed a theoretical model in which dingo populations may fluctuate between three main states: (A) below carrying capacity and socially fractured, (B) above carrying capacity and socially fractured, or (C) at carrying capacity and socially stable. We predicted that lethal control would drive dingoes into the unstable states A or B, and that relaxation of control would allow recovery towards C. We tested our predictions by surveying relative abundance (track density) and indicators of social stability (scent-marking and howling) at seven sites in the arid zone subject to differing degrees of control. We also monitored changes in dingo abundance and social stability following relaxation and intensification of control. Sites where dingoes had been controlled within the previous two years were characterized by low scent-marking activity, but abundance was similar at sites with and without control. Signs of social stability steadily increased the longer an area was allowed to recover from control, but change in abundance did not follow a consistent path. Comparison of abundance and stability among all sites and years demonstrated that control severely fractures social groups, but that the effect of control on abundance was neither consistent nor predictable. Management decisions involving large social predators must therefore consider social stability to ensure their conservation and ecological functioning.

Predator control promotes invasive dominated ecological states

Invasive species are regarded as one of the top five drivers of the global extinction crisis. In response, extreme measures have been applied in an attempt to control or eradicate invasives, with little success overall. We tested the idea that state shifts to invasive dominance are symptomatic of losses in ecosystem resilience, due to the suppression of apex predators. This concept was investigated in Australia where the high rate of mammalian extinctions is largely attributed to the destructive influence of invasive species. Intensive pest control is widely applied across the continent, simultaneously eliminating Australia’s apex predator, the dingo (Canis lupus dingo). We show that predator management accounts for shifts between two main ecosystem states. Lethal control fractures dingo social structure and leads to bottom-up driven increases in invasive mesopredators and herbivores. Where control is relaxed, dingoes re-establish top–down regulation of ecosystems, allowing for the recovery of biodiversity and productivity.

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.

Effects of predator control on behaviour of an apex predator and indirect consequences for mesopredator suppression

1. Apex predators can benefit ecosystems through top–down control of mesopredators and herbivores. However, apex predators are often subject to lethal control aimed at minimizing attacks on livestock. Lethal control can affect both the abundance and behaviour of apex predators. These changes could in turn influence the abundance and behaviour of mesopredators.

2. We used remote camera surveys at nine pairs of large Australian rangeland properties, comparing properties that controlled dingoes Canis lupus dingo with properties that did not, to test the effects of predator control on dingo activity and to evaluate the responses of a mesopredator, the feral cat Felis catus.

3. Indices of dingo abundance were generally reduced on properties that practiced dingo control, in comparison with paired properties that did not, although the effect size of control was variable. Dingoes in uncontrolled populations were crepuscular, similar to major prey. In populations subject to control, dingoes became less active around dusk, and activity was concentrated in the period shortly before dawn.

4. Shifts in feral cat abundance indices between properties with and without dingo control were inversely related to corresponding shifts in indices of dingo abundance. There was also a negative relationship between predator visitation rates at individual camera stations, suggesting cats avoided areas where dingoes were locally common. Reduced activity by dingoes at dusk was associated with higher activity of cats at dusk.

5. Our results suggest that effective dingo control not only leads to higher abundance of feral cats, but allows them to optimize hunting behaviour when dingoes are less active. This double effect could amplify the impacts of dingo control on prey species selected by cats. In areas managed for conservation, stable dingo populations may thus contribute to management objectives by restricting feral cat access to prey populations.

6. Synthesis and applications. Predator control not only reduces indices of apex predator abundance but can also modify their behaviour. Hence, indicators other than abundance, such as behavioural patterns, should be considered when estimating a predator's capacity to effectively interact with lower trophic guilds. Changes to apex predator behaviour may relax limitations on the behaviour of mesopredators, providing enhanced access to resources and prey.

The dingo and biodiversity conservation : response to Fleming et al. (2012)

Several authors have recently argued that dingoes could be used to help conserve biodiversity in Australia. Fleming et al. (2012) [Australian Mammalogy 34, 119–131] offer the alternative view that restoration of dingo predation is unlikely to help native species, and is more likely to do harm. We think many of the arguments used by Fleming et al. to reach that conclusion are either unsound or beside the point, and we explain why.

Conservation gone to the dogs : when canids rule the beach in small coastal reserves

On most developed coastlines, dunes backing ocean beaches constitute an urbanised landscape mosaic containing remnant pockets of small conservation areas. Urbanised beaches are also prime sites for domestic dogs, known to be environmentally harmful in many other settings. It is unknown, however, whether small, protected parcels of dune are adequate for biological conservation and whether dogs compromise their functional conservation objectives. Here we examine, for two small (2 km ocean boundary) reserves in Eastern Australia abutting an urban area, whether such small reserves can continue to function as effective conservation instruments on ocean beaches, using scavenger community composition and efficiency to assess ecosystem function. Two non-native species of canids—domestic dogs (Canis lupus familiaris) and red foxes (Vulpes vulpes)—were ubiquitous and numerous inside conservation areas, to the point of having become the most abundant vertebrate scavengers at the beach-dune interface, outcompeting native scavengers for wave-cast carrion. Dogs and foxes have effectively supplanted raptors, normally abundant on non-urban beaches in the region, and other avian scavengers, as the principal consumers of animal carcasses both inside the declared reserves and at the urban beach. Whilst the ecological threats posed by foxes are widely and intensively addressed in Australia in the form of fox-control programs, dog controls are less common and stringent. Our data emphasize, however, that managing domestic dogs may be required to the same extent in order to maintain key forms and functions in coastal reserves situated close to urban areas.

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.

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.