Exercise therapy for prevention of falls in people with Parkinson's disease: A protocol for a randomised controlled trial and economic evaluation

Background

People with Parkinson's disease are twice as likely to be recurrent fallers compared to other older people. As these falls have devastating consequences, there is an urgent need to identify and test innovative interventions with the potential to reduce falls in people with Parkinson's disease. The main objective of this randomised controlled trial is to determine whether fall rates can be reduced in people with Parkinson's disease using exercise targeting three potentially remediable risk factors for falls (reduced balance, reduced leg muscle strength and freezing of gait). In addition we will establish the cost effectiveness of the exercise program from the health provider's perspective.

Methods/Design

230 community-dwelling participants with idiopathic Parkinson's disease will be recruited. Eligible participants will also have a history of falls or be identified as being at risk of falls on assessment. Participants will be randomly allocated to a usual-care control group or an intervention group which will undertake weight-bearing balance and strengthening exercises and use cueing strategies to address freezing of gait. The intervention group will choose between the home-based or support group-based mode of the program. Participants in both groups will receive standardized falls prevention advice. The primary outcome measure will be fall rates. Participants will record falls and medical interventions in a diary for the duration of the 6-month intervention period. Secondary measures include the Parkinson's Disease Falls Risk Score, maximal leg muscle strength, standing balance, the Short Physical Performance Battery, freezing of gait, health and well being, habitual physical activity and positive and negative affect schedule.

Discussion

No adequately powered studies have investigated exercise interventions aimed at reducing falls in people with Parkinson's disease. This trial will determine the effectiveness of the exercise intervention in reducing falls and its cost effectiveness. This pragmatic program, if found to be effective, has the potential to be implemented within existing community services.

Trial registration

The protocol for this study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12608000303347).     

Effects of Ethanol, Temperature, and Endogenous Regulatory Factors on the Characteristics of Striatal Opiate Receptors

Ethanol can alter the affinity of mouse striatal opiate receptors for their ligands, and the present studies were aimed at determining the importance of the receptor microenvironment for this effect of ethanol. Changing the temperature of the binding assay, and thus altering the properties of neuronal membrane lipids, resulted in changes in the observed affinity of striatal binding sites for dihydromorphine (DHM), but not for D-Ala2, D-Leu5-enkephalin (ENK). The changes in temperature also differentially altered the response of the two binding sites to ethanol. Two other factors that regulate opiate receptor affinity, Na+ and GTP, also affected the response to ethanol. High concentrations of ethanol were more effective at decreasing receptor affinity for both DHM and ENK when the binding assays were performed in the presence of GTP or Na+. In addition, at 37 degrees C and in the presence of GTP or Na+, DHM binding, but not ENK binding, was significantly inhibited by a low, physiologically attainable concentration of ethanol. Our results suggest that the response of opiate receptors to ethanol is influenced by the microenvironment of the receptors, including the physical state of the membrane lipids and/or by the nature of the interactions of receptors with "coupling proteins" within the membrane. The differential responses of mu and delta receptors to temperature and to ethanol suggest that these receptors reside in specific membrane environments. Under physiological conditions, several different factors may contribute to a selective action of ethanol on particular subtypes of opiate receptors.     

The action of exogenous gibberellic acid on protein and mRNA in germinating castor bean seeds

Gibberellic acid (GA₃) stimulates water uptake in castor beans and increases the activity of certain enzymes associated with lipid mobilisation.The effect of the GA₃ on the enzymes is possibly due to a general effect of the growth substance on protein synthesis. Gibberellic acid advanced the appearance of rRNA and poly (A⁺)RNA in castor bean endosperms without specifically stimulating the synthesis of particular mRNA species. Thus these increased levels of mRNA and rRNA may act synergistically to affect the rate of a predetermined pattern of protein synthesis.Abbreviations SDS sodium dodecyl sulphate - GA₃ gibberellic acid - PAGE polyacrylamide gel electrophoresis     

High-resolution array CGH increases heterogeneity tolerance in the analysis of clinical samples

Recent advances in array comparative genomic hybridization (array CGH) technology are revolutionizing our understanding of tumor genomes. Marker-based arrays enable rapid survey at megabase intervals, while tiling path arrays examine the entire genome in unprecedented detail. Tumor biopsies are typically small and contain infiltrating stromal cells, requiring tedious microdissection. Tissue heterogeneity is a major barrier to high-throughput profiling of tumor genomes and is also an important consideration for the introduction of array CGH to clinical settings. We propose that increasing array resolution will enhance detection sensitivity in mixed tissues and as a result significantly reduce microdissection requirements. In this study, we first simulated normal cell contamination to determine the heterogeneity tolerance of array CGH and then validated this detection sensitivity model on cancer specimens using the newly developed submegabase resolution tiling-set (SMRT) array, which spans the human genome with 32,433 overlapping BAC clones.     

The importance of starch biosynthesis in the wrinkled seed shape character of peas studied by Mendel

The wrinkled-seed mutant (rr) of pea (Pisum sativum L.) arose through mutation of the gene encoding starch-branching enzyme isoform I (SBE1) by insertion of a transposon-like element into the coding sequence. Two isoforms of starch-branching enzyme have been documented in the developing pea embryo. The second isoform, SBEII, is expressed towards the later stages of embryo development while SBEI is expressed highly in the early stages. Due to mutation of SBEI the total amount of starch and the proportion of amylopectin, a branched starch polymer, are greatly reduced in the wrinkled (rr) line as compared to that in the wild-type, round (RR) line. Consequently, the level of sucrose in the rr line is nearly two fold that of the RR line. Increased sucrose concentration in the developing embryos of this mutant line causes increased uptake of water and thereby increases the cell size and fresh weight. During seed maturation in these mutant seeds a greater loss of water occurs. As a result, the wrinkled seed phenotype develops. Besides this morphological variation, the mutation also causes changes in the amount of lipid and of one storage protein, legumin. This review article discusses the role of the SBEI enzyme in causing such metabolic changes in the developing embryos with the implication that metabolism can play a central role in plant development.     

Dual Catalytic Activity of Hydroxycinnamoyl-Coenzyme A Quinate Transferase from Tomato Allows It to Moonlight in the Synthesis of Both Mono- and Dicaffeoylquinic Acids

Tomato (Solanum lycopersicum), like other Solanaceous species, accumulates high levels of antioxidant caffeoylquinic acids, which are strong bioactive molecules and protect plants against biotic and abiotic stresses. Among these compounds, the monocaffeoylquinic acids (e.g. chlorogenic acid [CGA]) and the dicaffeoylquinic acids (diCQAs) have been found to possess marked antioxidative properties. Thus, they are of therapeutic interest both as phytonutrients in foods and as pharmaceuticals. Strategies to increase diCQA content in plants have been hampered by the modest understanding of their biosynthesis and whether the same pathway exists in different plant species. Incubation of CGA with crude extracts of tomato fruits led to the formation of two new products, which were identified by liquid chromatography-mass spectrometry as diCQAs. This chlorogenate:chlorogenate transferase activity was partially purified from ripe fruit. The final protein fraction resulted in 388-fold enrichment of activity and was subjected to trypsin digestion and mass spectrometric sequencing: a hydroxycinnamoyl-Coenzyme A:quinate hydroxycinnamoyl transferase (HQT) was selected as a candidate protein. Assay of recombinant HQT protein expressed in Escherichia coli confirmed its ability to synthesize diCQAs in vitro. This second activity (chlorogenate:chlorogenate transferase) of HQT had a low pH optimum and a high K_m for its substrate, CGA. High concentrations of CGA and relatively low pH occur in the vacuoles of plant cells. Transient assays demonstrated that tomato HQT localizes to the vacuole as well as to the cytoplasm of plant cells, supporting the idea that in this species, the enzyme catalyzes different reactions in two subcellular compartments.The importance of plant-based foods in preventing or reducing the risk of chronic disease has been widely demonstrated (Martin et al., 2011, 2013). In addition to vitamins, a large number of other nutrients in plant-based foods promote health and reduce the risk of chronic diseases; these are often referred to as phytonutrients. The presence of phytonutrients in fruit and vegetables is of significant nutritional and therapeutic importance, as many have been found to possess strong antioxidant activity (Rice-Evans et al., 1997). Phenolics are the most widespread dietary antioxidants and caffeoylquinic acids, such as chlorogenic acid (CGA), dicaffeoylquinic acids (diCQAs), and tricaffeoylquinic acids (triCQAs), play important roles in promoting health (Clifford, 1999; Niggeweg et al., 2004). CGA limits low density lipid oxidation (Meyer et al., 1998), diCQAs possess antihepatotoxic activity (Choi et al., 2005), and triCQAs reduce the blood Glc levels of diabetic rats (Islam, 2006). diCQA derivatives have been shown to protect humans from various kinds of diseases; diCQAs suppress melanogenesis effectively (Kaul and Khanduja, 1998), show anti-inflammatory activity in vitro (Peluso et al., 1995), and exhibit a selective inhibition of HIV replication (McDougall et al., 1998). The physiological effects of caffeoylquinic acid derivatives with multiple caffeoyl groups are generally greater than those of monocaffeoylquinic acids, perhaps because the antioxidant activity is largely determined by the number of hydroxyl groups present on the aromatic rings (Wang et al., 2003; Islam, 2006). Furthermore, both diCQAs and triCQAs may function as inhibitors of the activity of HIV integrase, which catalyzes the insertion of viral DNA into the genome of host cells (McDougall et al., 1998; Slanina et al., 2001; Gu et al., 2007).CGA is the major soluble phenolic in Solanaceous crops (Clifford, 1999) and the major antioxidant in the average U.S. diet (Luo et al., 2008), while different isomers of diCQAs have been identified in many crops such as coffee (Coffea canephora), globe artichoke (Cynara cardunculus), tomato (Solanum lycopersicum), lettuce (Lactuca sativa), and sweet potato (Ipomoea batatas; Clifford, 1999; Islam, 2006; Moco et al., 2006, 2007; Moglia et al., 2008). In tomato, CGA accounts for 75% and 35% of the total phenolics in mature green and ripe fruit, respectively, amounting to 2 to 40 mg 100 g^–1 dry weight (DW), although levels decline after ripening and during postharvest storage (Slimestad and Verheul, 2009). diCQAs and triCQAs also accumulate in tomato fruit (diCQAs, approximately 2 mg 100 g^–1 DW; and triCQAs, 1–2 mg 100 g^–1 DW; Chanforan et al., 2012).Three pathways (Villegas and Kojima, 1986; Hoffmann et al., 2003; Niggeweg et al., 2004) have been proposed for the synthesis of CGA: (1) the direct pathway involving caffeoyl-CoA transesterification with quinic acid by hydroxycinnamoyl-Coenzyme A:quinate hydroxycinnamoyl transferase (HQT; Niggeweg et al., 2004; Comino et al., 2009; Menin et al., 2010; Sonnante et al., 2010); (2) the route by which p-coumaroyl-CoA is first transesterified with quinic acid via hydroxycinnamoyl-Coenzyme A transferase (HCT) acyltransferase (Hoffmann et al., 2003; Comino et al., 2007), followed by the hydroxylation of p-coumaroyl quinate to 5-caffeoylquinic acid, catalyzed by C3′H (p-coumaroyl-3-hydroxylase; Schoch et al., 2001; Mahesh et al., 2007; Moglia et al., 2009); and (3) the use of caffeoyl-glucoside as the acyl-donor (Villegas and Kojima, 1986). In tomato, the synthesis of CGA involves transesterification of caffeoyl-CoA with quinic acid by HQT (Niggeweg et al., 2004).To date, it is not clear whether diCQAs are derived directly from the monocaffeoylquinic acids (such as CGA) through a second acyltransferase reaction involving an acyl-CoA or not, although their structural similarity provides good a priori evidence supporting this hypothesis. Recently the in vitro synthesis of 3,5-diCQA from CGA and CoA by HCT from coffee has been reported (Lallemand et al., 2012). By contrast, in sweet potato, an enzyme that catalyzes the transfer of the caffeoyl moiety of CGA to another molecule of CGA, leading to the synthesis of isochlorogenate (3,5-di-O-caffeoylquinate), has been described, but the corresponding gene has not been identified (Villegas and Kojima, 1986).We report a chlorogenate:chlorogenate transferase (CCT) activity leading to the synthesis of diCQAs in tomato fruits and describe how alternative catalysis, by a single enzyme, leads to the production of both CGA and diCQA in different cellular compartments.