Role of immune-inflammatory and oxidative and nitrosative stress pathways in the etiology of depression: therapeutic implications

Accumulating data have led to a re-conceptualization of depression that emphasizes the role of immuneinflammatory processes, coupled to oxidative and nitrosative stress (O&NS). These in turn drive the production of neuroregulatory tryptophan catabolites (TRYCATs), driving tryptophan away from serotonin, melatonin, and Nacetylserotonin production, and contributing to central dysregulation. This revised perspective better encompasses the diverse range of biological changes occurring in depression and in doing so provides novel and readily attainable treatment targets, as well as potential screening investigations prior to treatment initiation. We briefly review the role that immune-inflammatory, O&NS, and TRYCAT pathways play in the etiology, course, and treatment of depression. We then discuss the pharmacological treatment implications arising from this, including the potentiation of currently available antidepressants by the adjunctive use of immune- and O&NS- targeted therapies. The use of such a frame of reference and the treatment benefits attained are likely to have wider implications and utility for depression-associated conditions, including the neuroinflammatory and (neuro)degenerative disorders.

Use of the wound-inducible NtQPT2 promoter from Nicotiana tabacum for production of a plant-made vaccine

The wound-inducible quinolinate phosphoribosyl transferase promoter from Nicotiana tabacum (NtQPT2) was assessed for its capacity to produce B-subunit of the heat-labile toxin (LTB) from enterotoxigenic Escherichia coli in transgenic plant tissues. Comparisons were made with the widely used and constitutive Cauliflower Mosaic Virus 35S (CaMV35S) promoter. The NtQPT2 promoter produced somewhat lower average concentrations of LTB protein per unit weight of hairy root tissue but allowed better growth thereby producing similar or higher overall average yields of LTB per culture batch. Transgenic tobacco plants containing the NtQPT2-LTB construct contained LTB protein in roots but not leaves. Moreover, wounding NtQPT2-LTB transgenic plants, by removal of apices, resulted in an approximate 500% increase in LTB levels in roots when analysed several days later. CaMV35S-LTB transgenic plants contained LTB protein in leaves and roots but wounding made no difference to their LTB content.

Is lithium in a class of its own? A brief profile of its clinical use

Lithium is a unique and effective psychotropic agent with a long-standing history of clinical use yet it is increasingly overlooked in lieu of newer agents. The purpose of the present paper was to succinctly review the therapeutic profile of lithium particularly with respect to the treatment of mood disorders and consider its unique properties and clinical utility. A comprehensive literature review pertaining to lithium was undertaken using electronic database search engines to identify relevant clinical trials, meta-analyses and Cochrane reviews. In addition articles and book chapters known to the authors were carefully reviewed, and the authors appraised published guidelines. The evidence from these sources was rated using National Health and Medical Research Council evidence levels and synthesized according to phenotype and mood states. In addition, the authors have drawn upon published guidelines and their own clinical experience. Lithium has specificity for mood disorders with proven efficacy in the treatment of both unipolar depression and bipolar disorder. The recommendations are based predominantly on Level I evidence, but its clinical use has to be tempered against potential side-effects and the need for ongoing monitoring. In practice, lithium should be considered a first-line option in bipolar disorder, especially in prophylaxis and when onset of action is not an imperative. Lithium has been in use in modern medicine for 60 years and as such has been tried and tested across the full range of mood disorders. Arguably, lithium is the only true mood stabilizer and because of its unique properties is in a class of its own.

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 1 historical and established therapies

Multiple sclerosis (MS) is a potentially life-changing immune mediated disease of the central nervous system. Until recently, treatment has been largely confined to acute treatment of relapses, symptomatic therapies and rehabilitation. Through persistent efforts of dedicated physicians and scientists around the globe for 160 years, a number of therapies that have an impact on the long term outcome of the disease have emerged over the past 20 years. In this three part series we review the practicalities, benefits and potential hazards of each of the currently available and emerging treatment options for MS. We pay particular attention to ways of abrogating the risks of these therapies and provide advice on the most appropriate indications for using individual therapies. In Part 1 we review the history of the development of MS therapies and its connection with the underlying immunobiology of the disease. The established therapies for MS are reviewed in detail and their current availability and indications in Australia and New Zealand are summarised. We examine the evidence to support their use in the treatment of MS.

The use of metabolomics in the study of metals in biological systems

Metabolomics may be defined as the comprehensive quantitative and/or qualitative analysis of all metabolites present in a bio-fluid, cell, tissue, or organism. It is essentially the study of biochemical phenotypes (or metabotypes). Metabolic profiles are context dependent, and vary in response to a variety of factors including environment and environmental stimuli, health status, disease and a myriad of other factors; as such, metabolomics has been applied to a wide range of fields and has been increasingly utilised to the study of the roles played by metals in a range of biological systems as well as, encouragingly, in understanding the underlying biochemical mechanisms. The role of metals (and metalloids) in biological organisms is complex and the majority of studies in this area have been performed in plants but the fields of natural product chemistry, human health and even bacterial corrosion of water distribution systems have been investigated using this technique. In this review some of the novel approaches in which the metabolomics toolbox has been used to unravel the roles of metals and metalloids in a range of biological systems are discussed and suggestions made for future research.

Adherence to therapeutic guidelines for patients with community-acquired pneumonia in Australian hospitals

Community-acquired pneumonia (CAP) is a significant cause of morbidity and mortality, particularly in elderly patients, and is associated with a considerable economic burden on the healthcare system. The combination of high incidence and substantial financial costs necessitate accurate diagnosis and appropriate management of patients admitted with CAP. This article will discuss the rates of adherence to clinical guidelines, the use of severity scoring tools and the appropriateness of antimicrobial prescribing for patients diagnosed with CAP. The authors maintain that awareness of national and hospital guidelines is imperative to complement the physicians' clinical judgment with evidence-based recommendations. Increased use of pneumonia severity assessment tools and greater adherence to therapeutic guidelines will enhance concordant antimicrobial prescribing for patients with CAP. A robust and multifaceted educational intervention, in combination with antimicrobial stewardship programs, may enhance compliance of CAP guidelines in clinical practice in Australia.

Nonparametric discovery of learning patterns and autism subgroups from therapeutic data

Autism Spectrum Disorder (ASD) is growing at a staggering rate, but, little is known about the cause of this condition. Inferring learning patterns from therapeutic performance data, and subsequently clustering ASD children into subgroups, is important to understand this domain, and more importantly to inform evidence-based intervention. However, this data-driven task was difficult in the past due to insufficiency of data to perform reliable analysis. For the first time, using data from a recent application for early intervention in autism (TOBY Play pad), whose download count is now exceeding 4500, we present in this paper the automatic discovery of learning patterns across 32 skills in sensory, imitation and language. We use unsupervised learning methods for this task, but a notorious problem with existing methods is the correct specification of number of patterns in advance, which in our case is even more difficult due to complexity of the data. To this end, we appeal to recent Bayesian nonparametric methods, in particular the use of Bayesian Nonparametric Factor Analysis. This model uses Indian Buffet Process (IBP) as prior on a binary matrix of infinite columns to allocate groups of intervention skills to children. The optimal number of learning patterns as well as subgroup assignments are inferred automatically from data. Our experimental results follow an exploratory approach, present different newly discovered learning patterns. To provide quantitative results, we also report the clustering evaluation against K-means and Nonnegative matrix factorization (NMF). In addition to the novelty of this new problem, we were able to demonstrate the suitability of Bayesian nonparametric models over parametric rivals.

Evolutionary history and leaf succulence as explanations for medicinal use in aloes and the global popularity of Aloe vera

BACKGROUND: Aloe vera supports a substantial global trade yet its wild origins, and explanations for its popularity over 500 related Aloe species in one of the world's largest succulent groups, have remained uncertain. We developed an explicit phylogenetic framework to explore links between the rich traditions of medicinal use and leaf succulence in aloes. RESULTS: The phylogenetic hypothesis clarifies the origins of Aloe vera to the Arabian Peninsula at the northernmost limits of the range for aloes. The genus Aloe originated in southern Africa ~16 million years ago and underwent two major radiations driven by different speciation processes, giving rise to the extraordinary diversity known today. Large, succulent leaves typical of medicinal aloes arose during the most recent diversification ~10 million years ago and are strongly correlated to the phylogeny and to the likelihood of a species being used for medicine. A significant, albeit weak, phylogenetic signal is evident in the medicinal uses of aloes, suggesting that the properties for which they are valued do not occur randomly across the branches of the phylogenetic tree. CONCLUSIONS: Phylogenetic investigation of plant use and leaf succulence among aloes has yielded new explanations for the extraordinary market dominance of Aloe vera. The industry preference for Aloe vera appears to be due to its proximity to important historic trade routes, and early introduction to trade and cultivation. Well-developed succulent leaf mesophyll tissue, an adaptive feature that likely contributed to the ecological success of the genus Aloe, is the main predictor for medicinal use among Aloe species, whereas evolutionary loss of succulence tends to be associated with losses of medicinal use. Phylogenetic analyses of plant use offer potential to understand patterns in the value of global plant diversity.

The therapeutic alliance and personality dysfunction in offending behaviour programs

 Therapists in offending behaviour programs use a range of strategies to develop the therapeutic alliance to promote treatment collaboration. They described significant difficulties, however, in responding to personality dysfunction. Analysis of treatment sessions revealed therapists often attempted to engage clients but did not often use ruptures in the alliance as therapeutic opportunities or attend to withdrawn clients. Recommendations are made to better support correctional therapists utilise the alliance to maximise treatment

Exergaming as a viable therapeutic tool to improve static and dynamic balance among older adults and people with idiopathic Parkinson's disease: a systematic review and meta-analysis

The use of virtual reality games (known as "exergaming") as a neurorehabilitation tool is gaining interest. Therefore, we aim to collate evidence for the effects of exergaming on the balance and postural control of older adults and people with idiopathic Parkinson's disease (IPD). Six electronic databases were searched, from inception to April 2015, to identify relevant studies. Standardized mean differences (SMDs) and 95% confidence intervals (CI) were used to calculate effect sizes between experimental and control groups. I (2) statistics were used to determine levels of heterogeneity. 325 older adults and 56 people with IPD who were assessed across 11 -studies. The results showed that exergaming improved static balance (SMD 1.069, 95% CI 0.563-1.576), postural control (SMD 0.826, 95% CI 0.481-1.170), and dynamic balance (SMD -0.808, 95% CI -1.192 to -0.424) in healthy older adults. Two IPD studies showed an improvement in static balance (SMD 0.124, 95% CI -0.581 to 0.828) and postural control (SMD 2.576, 95% CI 1.534-3.599). Our findings suggest that exergaming might be an appropriate therapeutic tool for improving balance and postural control in older adults, but more -large-scale trials are needed to determine if the same is true for people with IPD.

Nanostructured liquid crystalline particle assisted delivery of 2,4-dichlorophenoxyacetic acid to weeds, crops and model plants

Routine agricultural practices are heavily dependent on the use of surfactants, many of which are toxic to humans and detrimental to the environment. In proof of concept work we have previously shown the potential of nanostructured liquid crystalline particles (NLCP) to safely interact with plant leaf cuticular surfaces with minimal impact on epicuticular waxes. Here we demonstrate the use of NLCP to effectively deliver the auxin herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) to plant leaves in laboratory and field studies. In the laboratory, the physiological stress responses of lupin, Lupinus angustifolius (L.) (Fabaceae) towards NLCP spray applications were shown to be much reduced in comparison with application of two common surfactants. Phytotoxicity assays of 2,4-D loaded NLCP were used to validate the herbicidal effects on Arabidopsis thaliana (L.) Heynth. (Brassicaceae) and established a similarity with that of surfactant assisted 2,4-D delivery when tested at a concentration of 0.1%. Field trials were conducted to test the efficacy of NLCP-assisted delivery of 2,4-D in comparison with commercial surfactants for the control of the invasive weed wild radish, Raphanus raphanistrum (L.) (Brassicaceae), in wheat, Triticum aestivum (L.) (Poaceae) crop fields. Compared against Estercide 800, a commercially available 2,4-D formulation, NLCP assisted delivery of 2,4-D was effective at low concentrations of 0.03% and 0.06%. The crop yield remained similar for all the tested concentrations and formulations of 2,4-D loaded NLCP and Estercide 800. This is the first report to directly show that, as an alternative to conventional methods, NLCP can be used under both laboratory and field conditions to successfully delivery an agrochemical.

The use of mixed methods in drug discovery: integrating qualitative methods into clinical trials

Contemporary methods in clinical trials are pivoted around hypothesis confirmation, not generation. This is a problem for new drug discovery, since the pharmacokinetic or receptor profile of most novel agents do not link to pathophysiology, which is very poorly understood. Therefore, it is difficult to impute the therapeutic potential of a candidate agent. Most psychotropic agents were discovered serendipitously, either through careful clinical observation or by researchers finding unexpected associations in datasets. Methods that increase the ability to detect latent signals in data are needed. These include mixed methods that incorporate qualitative methods into randomized controlled trials.

This chapter proposes a methodology for the integration of mixed methods in clinical trials, fusing qualitative and quantitative methods, and presents an exemplar using this approach.

Mixed methods show potential for signal detection, hypothesis generation, and associations that may be otherwise undetected in traditional clinical trials.

Metal and metalloid containing natural products and a brief overview of their applications in biology, biotechnology and biomedicine

Bioinorganic natural product chemistry is a relatively unexplored but rapidly developing field with enormous potential for applications in biology, biotechnology (especially in regards to nanomaterial development, synthesis and environmental cleanup) and biomedicine. In this review the occurrence of metals and metalloids in natural products and their synthetic derivatives are reviewed. A broad overview of the area is provided followed by a discussion on the more common metals and metalloids found in natural sources, and an overview of the requirements for future research. Special attention is given to metal hyperaccumulating plants and their use in chemical synthesis and bioremediation, as well as the potential uses of metals and metalloids as therapeutic agents. The potential future applications and development in the field are also discussed.