Cer survival in Utah by age and state. Statistics in Medicine

Cer survival in Utah by age and state. Statistics in Medicine 21, 895?20. VAUPEL J. W., M ANTON , K. G. AND S TALLARD , E. (1979). The impact of heterogeneity in individual frailty on the dynamics of mortality. Demography 16, 439?54. W RITING G ROUP F OR THE W OMEN ‘ S H EALTH I NITIATIVE I NVESTIGATORS (2002). Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women’s health initiative randomized controlled trial. Journal of the American Medical Association 288, 321?33. YANG , S. AND P RENTICE , R. L. (2005). Semiparametric analysis of short-term and long-term hazard ratios with two-sample survival data. Biometrika 92, 1?7. Z ENG , D. AND L IN , D. Y. (2007). Maximum likelihood estimation in semiparametric regression models with censored data. Journal of the Royal Statistical Society, Series B 69, 507?64. [Received October 21, 2009; revised August 23, 2010; accepted for publication August 24, 2010]
Parkinson’s disease (PD) is a common neurodegenerative movement disorder with clinical features including bradykinesia, rigidity and resting tremor. PD histopathological hallmarks are the loss of dopaminergic neurons in the substantia nigra and Lewy pathology. The latter is characterized by fibrillar a-synuclein (aSN) aggregates that are microscopically visible and referred to as Lewy bodies (LB) and Lewy neurites. This a-synuclein proteinopathy is often widespread and affects not only dopaminergic neurons in the substantia nigra but also neurons in other brainstem nuclei, the cortex, the spinal cord and the gastrointestinal nervous system [1,2,3]. The first mutation causing PD was discovered in the aSNencoding gene (SNCA) [4]. Since then, many more PD loci including leucine-rich repeat kinase-2 (LRRK2) have been discovered through linkage analysis or genome-wide association studies (GWAS) [5,6,7,8,9,10,11,12,13]. Furthermore, polymorphic variants of genes including SNCA, LRRK2 and microtubuleassociated protein Tau (MAPT) have emerged as susceptibility factors associated with an increased risk to develop PD [14,15,16,17,18]. LRRK2 mutations cause late-onset L868275 site autosomal dominant PD that is clinically indistinguishable from idiopathic PD. They account for approx. 4? of familiar and 1? of sporadic PDPLoS ONE | www.plosone.org[5,6,7,8,9,10,19,20]. In addition, LRRK2 has been implicated as a susceptibility factor in other Actidione dose diseases like Crohn’s disease [21,22,23], cancer [24,25] and leprosy [26] which could suggest unrecognized links between these disease pathophysiologies [27]. The most prominent PD-associated mutation G2019S was shown to result in increased kinase activity [28,29,30] and induce neuronal toxicity [31,32,33]. Such findings support the hypothesis that enhanced LRRK2 kinase function might suffice to evoke neuropathophysiological changes. They also raised hope that LRRK2 kinase inhibitors might be capable of halting disease progression in LRRK2(G2019S) and perhaps other LRRK2 mutation carriers. Although the enhanced kinase function of the LRRK2(G2019S) mutant is the prime suspect mechanism for carriers with this mutation to develop PD, the discovery by us and others of LRRK2-dependent phenotypes in kidney suggest that also steady-state abundance of the LRRK2 protein might play a determining role [30,34]. In patients with LRRK2 mutations and clinically manifest PD, the associated neuropathology is heterogeneous ranging from LB pathology with a variable burden of Tau neurofibrillary.Cer survival in Utah by age and state. Statistics in Medicine 21, 895?20. VAUPEL J. W., M ANTON , K. G. AND S TALLARD , E. (1979). The impact of heterogeneity in individual frailty on the dynamics of mortality. Demography 16, 439?54. W RITING G ROUP F OR THE W OMEN ‘ S H EALTH I NITIATIVE I NVESTIGATORS (2002). Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women’s health initiative randomized controlled trial. Journal of the American Medical Association 288, 321?33. YANG , S. AND P RENTICE , R. L. (2005). Semiparametric analysis of short-term and long-term hazard ratios with two-sample survival data. Biometrika 92, 1?7. Z ENG , D. AND L IN , D. Y. (2007). Maximum likelihood estimation in semiparametric regression models with censored data. Journal of the Royal Statistical Society, Series B 69, 507?64. [Received October 21, 2009; revised August 23, 2010; accepted for publication August 24, 2010]
Parkinson’s disease (PD) is a common neurodegenerative movement disorder with clinical features including bradykinesia, rigidity and resting tremor. PD histopathological hallmarks are the loss of dopaminergic neurons in the substantia nigra and Lewy pathology. The latter is characterized by fibrillar a-synuclein (aSN) aggregates that are microscopically visible and referred to as Lewy bodies (LB) and Lewy neurites. This a-synuclein proteinopathy is often widespread and affects not only dopaminergic neurons in the substantia nigra but also neurons in other brainstem nuclei, the cortex, the spinal cord and the gastrointestinal nervous system [1,2,3]. The first mutation causing PD was discovered in the aSNencoding gene (SNCA) [4]. Since then, many more PD loci including leucine-rich repeat kinase-2 (LRRK2) have been discovered through linkage analysis or genome-wide association studies (GWAS) [5,6,7,8,9,10,11,12,13]. Furthermore, polymorphic variants of genes including SNCA, LRRK2 and microtubuleassociated protein Tau (MAPT) have emerged as susceptibility factors associated with an increased risk to develop PD [14,15,16,17,18]. LRRK2 mutations cause late-onset autosomal dominant PD that is clinically indistinguishable from idiopathic PD. They account for approx. 4? of familiar and 1? of sporadic PDPLoS ONE | www.plosone.org[5,6,7,8,9,10,19,20]. In addition, LRRK2 has been implicated as a susceptibility factor in other diseases like Crohn’s disease [21,22,23], cancer [24,25] and leprosy [26] which could suggest unrecognized links between these disease pathophysiologies [27]. The most prominent PD-associated mutation G2019S was shown to result in increased kinase activity [28,29,30] and induce neuronal toxicity [31,32,33]. Such findings support the hypothesis that enhanced LRRK2 kinase function might suffice to evoke neuropathophysiological changes. They also raised hope that LRRK2 kinase inhibitors might be capable of halting disease progression in LRRK2(G2019S) and perhaps other LRRK2 mutation carriers. Although the enhanced kinase function of the LRRK2(G2019S) mutant is the prime suspect mechanism for carriers with this mutation to develop PD, the discovery by us and others of LRRK2-dependent phenotypes in kidney suggest that also steady-state abundance of the LRRK2 protein might play a determining role [30,34]. In patients with LRRK2 mutations and clinically manifest PD, the associated neuropathology is heterogeneous ranging from LB pathology with a variable burden of Tau neurofibrillary.

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