Australian data and meta-analysis lend support for alpha-synuclein (NACP-Rep1) as a risk factor for Parkinson's disease

It remains unclear whether genetic variants in SNCA (the alpha-synuclein gene) alter risk for sporadic Parkinson's disease (PD). The polymorphic mixed sequence repeat (NACP-Rep I) in the promoter region of SNCA has been previously examined as a potential susceptibility factor for PD with conflicting results. We report genotype and allele distributions at this locus from 369 PD cases and 370 control subjects of European Australian ancestry, with alleles designated as -1, 0, +1, +2, and +3 as previously described. Allele frequencies designated (0) were less common in Australian cases compared to controls (OR = 0.80, 95% CI 0.62-1.03). Combined analysis including all previously published ancestral European Rep1 data yielded a highly significant association between the 0 allele and a reduced risk for PD (OR = 0.79, 95% CI 0.70-0.89, p = 0.0001). Further study must now proceed to examine in detail this interesting and biologically plausible genetic association. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

Summation of semantic priming and complex sentence comprehension in Parkinson's disease

Research has suggested that the integrity of semantic processing may be compromised in Parkinson's disease (PD), which may account for difficulties in complex sentence comprehension. In order to investigate the time course and integrity of semantic activation in PD, 20 patients with PD and 23 healthy controls performed a lexical decision task based on the multi-priming paradigm. Semantic priming effects were measured across stimulus onset asynchronies of 250 ms, 600 ms, and 1200 ms. Further, PD participants performed an auditory comprehension task. The results revealed significantly different patterns of semantic priming for the PD group at the 250-ms and 1200-ms SOAs. In addition, a delayed time course of semantic activation was evident for PD patients with poor comprehension of complex sentences. These results provide further support to suggest that both automatic and controlled aspects of semantic activation may be compromised in PD. Furthermore, the results also suggest that some sentence comprehension deficits in PD may be related to a reduction in information processing speed.

Rho and vascular disease

The Rho family GTPases are regulatory molecules that link surface receptors to organisation of the actin cytoskeleton and play major roles in fundamental cellular processes. In the vasculature Rho signalling pathways are intimately involved in the regulation of endothelial barrier function, inflammation and transendothelial leukocyte migration, platelet activation, thrombosis and oxidative stress, as well as smooth muscle contraction, migration, proliferation and differentiation, and are thus implicated in many of the changes associated with atherogenesis. Indeed, it is believed that many of the beneficial, non-lipid lowering effects of statins occur as a result of their ability to inhibit Rho protein activation. Conversely, the Rho proteins can have beneficial effects on the vasculature, including the promotion of endothelial repair and the maintenance of SMC differentiation. Further identification of the mechanisms by which these proteins and their effectors act in the vasculature should lead to therapies that specifically target only the adverse effects of Rho signalling. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

MULTIPRED: A computational system for prediction of promiscuous HLA binding peptides

MULTIPRED is a web-based computational system for the prediction of peptide binding to multiple molecules ( proteins) belonging to human leukocyte antigens (HLA) class I A2, A3 and class II DR supertypes. It uses hidden Markov models and artificial neural network methods as predictive engines. A novel data representation method enables MULTIPRED to predict peptides that promiscuously bind multiple HLA alleles within one HLA supertype. Extensive testing was performed for validation of the prediction models. Testing results show that MULTIPRED is both sensitive and specific and it has good predictive ability ( area under the receiver operating characteristic curve A(ROC) > 0.80). MULTIPRED can be used for the mapping of promiscuous T-cell epitopes as well as the regions of high concentration of these targets termed T-cell epitope hotspots. MULTIPRED is available at http:// antigen.i2r.a-star.edu.sg/ multipred/.

Cognitive disorders and neurogenesis deficits in Huntington's disease mice are rescued by fluoxetine

Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeat encoding an extended polyglutamine tract in the huntingtin protein. Affected individuals display progressive motor, cognitive and psychiatric symptoms (including depression), leading to terminal decline. Given that transgenic HD mice have decreased hippocampal cell proliferation and that a deficit in neurogenesis has been postulated as an underlying cause of depression, we hypothesized that decreased hippocampal neurogenesis contributes to depressive symptoms and cognitive decline in HD. Fluoxetine, a serotonin-reuptake inhibitor commonly prescribed for the treatment of depression, is known to increase neurogenesis in the dentate gyrus of wild-type mouse hippocampus. Here we show that hippocampal-dependent cognitive and depressive-like behavioural symptoms occur in HD mice, and that the administration of fluoxetine produces a marked improvement in these deficits. Furthermore, fluoxetine was found to rescue deficits of neurogenesis and volume loss in the dentate gyrus of HD mice.

Cardiovascular disease and PPARdelta: Targeting the risk factors

Metabolism, in part, is regulated by the peroxisome proliferator-activated receptors (PPARs). The PPARs act as nutritional lipid sensors and three mammalian PPAR subtypes designated PPARalpha (NR1C1), PPARgamma (NR1C3) and PPARdelta (NR1C2) have been identified. This subgroup of nuclear hormone receptors binds DNA and controls gene expression at the nexus of pathways that regulate lipid and glucose homeostasis, energy storage and expenditure in an organ-specific manner. Recent evidence has demonstrated activation of PPARdelta in the major mass peripheral tissue (ie, adipose and skeletal muscle). It enhances glucose tolerance, insulin-stimulated glucose disposal, lipid catabolism, energy expenditure, cholesterol efflux and oxygen consumption. These effects positively influence the blood-lipid profile. Furthermore, PPARdelta activation produces a predominant type I/slow twitch/oxidative muscle fiber phenotype that leads to increased endurance, insulin sensitivity and resistance to obesity. PPARdelta has rapidly emerged as a potential target in the battle against dyslipidemia, insulin insensitivity, type II diabetes and obesity, with therapeutic efficacy in the treatment of cardiovascular disease risk factors. GW-501516 is currently undergoing phase II safety and efficacy trials in human volunteers for the treatment of dyslipidemia. The outcome of these clinical trials are eagerly awaited against a background of conflicting reports about cancer risks in genetically predisposed animal models. This review focuses on the potential pharmacological utility of selective PPARdelta agonists in the context of risk factors associated with metabolic and cardiovascular disease.

Zebrafish as a model for caveolin-associated muscle disease; caveolin-3 is required for myofibril organization and muscle cell patterning

Caveolae are an abundant feature of many animal cells. However, the exact function of caveolae remains unclear. We have used the zebrafish, Danio rerio, as a system to understand caveolae function focusing on the muscle-specific caveolar protein, caveolin-3 (Cav3). We have identified caveolin-1 (alpha and beta), caveolin-2 and Cav3 in the zebrafish. Zebrafish Cav3 has 72% identity to human CAV3, and the amino acids altered in human muscle diseases are conserved in the zebrafish protein. During embryonic development, cav3 expression is apparent by early segmentation stages in the first differentiating muscle precursors, the adaxial cells and slightly later in the notochord. cav3 expression appears in the somites during mid-segmentation stages and then later in the pectoral fins and facial muscles. Cav3 and caveolae are located along the entire sarcolemma of late stage embryonic muscle fibers, whereas beta-dystroglycan is restricted to the muscle fiber ends. Down-regulation of Cav3 expression causes gross muscle abnormalities and uncoordinated movement. Ultrastructural analysis of isolated muscle fibers reveals defects in myoblast fusion and disorganized myofibril and membrane systems. Expression of the zebrafish equivalent to a human muscular dystrophy mutant, CAV3P104L, causes severe disruption of muscle differentiation. In addition, knockdown of Cav3 resulted in a dramatic up-regulation of eng1a expression resulting in an increase in the number of muscle pioneer-like cells adjacent to the notochord. These studies provide new insights into the role of Cav3 in muscle development and demonstrate its requirement for correct intracellular organization and myoblast fusion.

Disease risk and mortality prediction in intensive care patients with pneumonia. Australian and New Zealand practice in intensive care (ANZPIC II)

This study of ventilated patients investigated pneumonia risk factors and outcome predictors in 476 episodes of pneumonia (48% community-acquired pneumonia, 24% hospital-acquired pneumonia, 28% ventilator-associated pneumonia) using a prospective survey in 14 intensive care units within Australia and New Zealand. For community acquired pneumonia, mortality increased with immunosuppression (OR 5.32, CI 95% 1.58-17.99, P < 0. 01), clinical signs of consolidation (OR 2.43, CI 95% 1.09-5.44, P = 0. 03) and Sepsis-Related Organ Failure Assessment (SOFA) scores (OR 1.19, CI 95% 1.08-1.30, P < 0. 001) but improved if appropriate antibiotic changes were made within three days of intensive care unit admission (OR 0.42, CI 95% 0.20-0.86, P = 0.02). For hospital-acquired pneumonia, immunosuppression (OR 6.98, CI 95% 1.16-42.2, P = 0.03) and non-metastatic cancer (OR 3.78, CI 95% 1.20-11.93, P = 0.02) were the principal mortality predictors. Alcoholism (OR 7.80, CI 95% 1.20-1750, P < 0.001), high SOFA scores (OR 1.44, CI 95% 1.20-1.75, P = 0.001) and the isolation of high risk organisms including Pseudomonas aeruginosa, Acinetobacter spp, Stenotrophomonas spp and methicillin resistant Staphylococcus aureus (OR 4.79, CI 95% 1.43-16.03, P = 0.01), were associated with increased mortality in ventilator-associated pneumonia. The use of non-invasive ventilation was independently protective against mortality for patients with community-acquired and hospital-acquired pneumonia (OR 0.35, CI 95% 0.18-0.68, P = 0.002). Mortality was similar for patients requiting both invasive and non-invasive ventilation and non-invasive ventilation alone (21% compared with 20% respectively, P = 0.56). Pneumonia risks and mortality predictors in Australian and New Zealand ICUs vary with pneumonia type. A history of alcoholism is a major risk factor for mortality in ventilator-associated pneumonia, greater in magnitude than the mortality effect of immunosuppression in hospital-acquired pneumonia or community-acquired pneumonia. Non-invasive ventilation is associated with reduced ICU mortality. Clinical signs of consolidation worsen, while rationalising antibiotic therapy within three days of ICU admission improves mortality for community-acquired pneumonia patients.

Nephron number, hypertension, renal disease, and renal failure

Essential hypertension is one of the most common diseases in the Western world, affecting about 26.4% of the adult population, and it is increasing (1). Its causes are heterogeneous and include genetic and environmental factors (2), but several observations point to an important role of the kidney in its genesis (3). In addition to variations in tubular transport mechanisms that could, for example, affect salt handling, structural characteristics of the kidney might also contribute to hypertension. The burden of chronic kidney disease is also increasing worldwide, due to population growth, increasing longevity, and changing risk factors. Although single-cause models of disease are still widely promoted, multideterminant or multihit models that can accommodate multiple risk factors in an individual or in a population are probably more applicable (4,5). In such a framework, nephron endowment is one potential determinant of disease susceptibility. Some time ago, Brenner and colleagues (6,7) proposed that lower nephron numbers predispose both to essential hypertension and to renal disease. They also proposed that hypertension and progressive renal insufficiency might be initiated and accelerated by glomerular hypertrophy and intraglomerular hypertension that develops as nephron number is reduced (8). In this review, we summarize data from recent studies that shed more light on these hypotheses. The data supply a new twist to possible mechanisms of the Barker hypothesis, which proposes that intrauterine growth retardation predisposes to chronic disease in later life (9). The review describes how nephron number is estimated and its range and some determinants and morphologic correlates. It then considers possible causes of low nephron numbers. Finally, associations of hypertension and renal disease with reduced nephron numbers are considered, and some potential clinical implications are discussed.

Interfaces between cardiovascular and kidney disease among Aboriginal Australians

Rates of kidney disease among several indigenous groups have been shown to be substantially higher than corresponding non-indigenous groups. This excess has been clearly shown among Aboriginal Australians with respect to both end-stage kidney disease and early kidney disease. Rates of cardiovascular disease among Aboriginal Australians are also very high, as are rates of diabetes, smoking, and possibly overweight and obesity. These factors have been traditionally linked with cardiovascular and renal disease as part of a broader metabolic syndrome. However, the links and interfaces between cardiovascular and kidney disease in this environment extend beyond these traditional factors. The factors associated with atherosclerosis have expanded in recent years to include markers of inflammation, some infection, antioxidants, and other non-traditional risk factors. Given the high rates of acute infection and poor living conditions endured by many indigenous people, one might expect these non-traditional risk factors to be highly prevalent. In this review, we explore the relationships between markers of inflammation, some serological markers of infection, and other selected markers and both cardiovascular and renal disease. In doing so, we demonstrate links between kidney and cardiovascular disease at a number of levels, beyond the traditional cardiovascular/renal risk factors. Many of these factors are beyond the control of the individual or even community; addressing these issues a broader focus and biopsychosocial model. (C) 2005 by the National Kidney Foundation, Inc.

Adult obesity and number of years lived with and without cardiovascular disease

Objective: To determine the differences in number of years lived free of cardiovascular disease (CVD) and number of years lived with CVD between men and women who were obese, pre-obese, or normal weight at 45 years of age. Research Methods and Procedures: We constructed multistate life tables for CVD, myocardial infarction, and stroke, using data from 2551 enrollees (1130 men) in the Framingham Heart Study who were 45 years of age. Results: Obesity and pre-obesity were associated with fewer number of years free of CVD, myocardial infarction, and stroke and an increase in the number of years lived with these diseases. Forty-five-year-old obese men with no CVD survived 6.0 years [95% confidence interval (CI), 4.1; 8.1] fewer than their normal weight counterparts, whereas, for women, the difference between obese and normal weight subjects was 8.4 years (95% CI: 6.2; 10.8). Obese men and women lived with CVD 2.7 (95% CI: 1.0; 4.4) and 1.4 years (95% CI: -0.3; 3.2) longer, respectively, than normal weight individuals. Discussion: In addition to reducing life expectancy, obesity before middle age is associated with a reduction in the number of years lived free of CVD and an increase in the number of years lived with CVD. Such information is paramount for preventive and therapeutic decision-making by individuals and practitioners alike.