PLA2G6 variant in Parkinson's disease.

PLA2G6 was reported recently as the causative gene for PARK14-linked autosomal recessive early-onset dystonia-parkinsonism. In a recent study in Singapore, heterozygous PLA2G6 p.P806R (c.

Severe obstructive sleep apnea increases cystatin C in clinically latent renal dysfunction.

Background: Obstructive sleep apnea (OSA) increases the risk of cardiovascular disease (CVD) and has been reported to be associated with chronic kidney disease (CKD). Recent studies have demonstrated that cystatin C is a prognostic biomarker of the risk of death and CVD even in patients without established CKD.

Methods: In a cross-sectional study, we enrolled 267 consecutive OSA patients without CKD who had an apnea-hypopnea index (AHI) ≥ 5 events per hour in overnight polysomnography.

[Vascular calcification and serum markers].

Recently, the multidetector computed tomography (CT) is available to measure quantitative analysis of coronary vascular calcification (coronary calcification score [CACscore]). Vascular calcification is recognized not only in the end stage of atherosclerosis but also in the early stage of atherosclerosis. Recent data suggested that bone- related factors are closely related to coronary artery disease and vascular calcification.

Rapid screening of ATP13A2 variant with high-resolution melting analysis.

Several genetic and environmental factors are involved in the pathogenesis of Parkinson's disease (PD). Recently, a novel variant of ATP13A2 (p.A746T) responsible for PARK9 was reported as a risk factor for PD in the Han-Chinese population.

Phenotypic spectrum of patients with PLA2G6 mutation and PARK14-linked parkinsonism.

Background: PLA2G6 is the causative gene for infantile neuroaxonal dystrophy, neurodegeneration associated with brain iron accumulation, and Karak syndrome. Based on previous reports, patients with PLA2G6 mutations could show axonal dystrophy, dystonia, dementia, and cerebellar signs. Recently, PLA2G6 was also reported as the causative gene for early-onset PARK14-linked dystonia-parkinsonism.

Clinical course of the first Asian family with Parkinsonism related to SNCA triplication.

Triplication of SNCA is a rare cause of familial Parkinson's disease compared with duplication. Its clinical course is believed to be more robust than duplication, though it is uncertain. Marked as the first among the Asian population, we identified a Japanese family (paternal grandfather, father, and son) with SNCA triplication based on genetic and clinical analyses.

Possible involvement of oxidative stress in 5-fluorouracil-mediated myelosuppression in mice.

Certain chemotherapeutic agents subject cells to oxidative stress, thereby promoting adverse effects. However, the molecular machinery governing 5-fluorouracil (5-FU)-mediated myelotoxicity is obscure. The purpose of this study was to clarify whether 5-FU-induced myelotoxicity is a cause of oxidative stress.

No evidence for pathogenic role of GIGYF2 mutation in Parkinson disease in Japanese patients.

Grb10-Interacting GYF Protein-2 (GIGYF2) is a candidate gene for PARK11 locus. To date, seven different GIGYF2 missense mutations have been identified in patients with familial Parkinson disease (PD) of European descent. To clarify the pathogenic role of GIGYF2 in PD, we analyzed the frequency of GIGYF2 mutations in 389 Japanese patients with PD (including 93 patients with late-onset familial PD, 276 with sporadic PD, and 20 with a single heterozygous mutation in the PD-associated genes), and 336 Japanese normal controls, by direct sequencing and/or high-resolution melting analysis.

Unexpected diversity of cellular immune responses against Nef and Vif in HIV-1-infected patients who spontaneously control viral replication.

Background: HIV-1-infected individuals who spontaneously control viral replication represent an example of successful containment of the AIDS virus. Understanding the anti-viral immune responses in these individuals may help in vaccine design. However, immune responses against HIV-1 are normally analyzed using HIV-1 consensus B 15-mers that overlap by 11 amino acids.

Mechanisms of genomic instabilities underlying two common fragile-site-associated loci, PARK2 and DMD, in germ cell and cancer cell lines.

Common fragile sites (CFSs) are specific chromosome regions that exhibit an increased frequency of breaks when cells are exposed to a DNA-replication inhibitor such as aphidicolin. PARK2 and DMD, the causative genes for autosomal-recessive juvenile Parkinsonism and Duchenne and Becker muscular dystrophy, respectively, are two very large genes that are located within aphidicolin-induced CFSs. Gross rearrangements within these two genes are frequently observed as the causative mutations for these diseases, and similar alterations within the large fragile sites that surround these genes are frequently observed in cancer cells.

Arterial stiffness and declines in individuals with normal renal function/early chronic kidney disease.

Objective: We evaluated the temporal association between arterial stiffening and the early stage of renal functional decline.

Methods: In 2053 Japanese employees with an estimated glomerular filtration rate (GFR) of > or = 60 ml/min/1.73 m(2) plus no proteinuria (40+/-8 years old) at the start, brachial-ankle pulse wave velocity (baPWV) and serum C-reactive protein (CRP) were measured before and after a 5-6-year follow-up period.

Association of serum cystatin C with pulse wave velocity, but not pressure wave reflection, in subjects with normal renal function or mild chronic kidney disease.

Background: This prospective cross-sectional study was conducted to clarify whether serum cystatin C levels might be associated with not only arterial stiffness, but also the pressure wave reflection, in middle-aged Japanese subjects with normal renal function or mild chronic kidney disease (CKD) (stage 1 or 2 CKD) (i.e., creatinine-based estimate of the glomerular filtration rate (eGFRcr) > or =60 ml/min/1.

Continuous smoking and progression of arterial stiffening: a prospective study.

Objectives: We prospectively and longitudinally determined the effects of smoking on the progression of arterial stiffening as well as the involvement of inflammation in this process.

Background: Smoking is an important avoidable risk factor for cardiovascular disease, and arterial stiffness might be involved in the pathophysiology. No prospective study has examined the effect of continuous smoking on the age-associated progression of arterial stiffening.

Parkinson's disease-related LRRK2 G2019S mutation results from independent mutational events in humans.

Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene have been identified in families with autosomal dominant Parkinson's disease (PD) and in sporadic cases; the G2019S mutation is the single most frequent. Intriguingly, the frequency of this mutation in PD patients varies greatly among ethnic groups and geographic origins: it is present at <0.1% in East Asia, approximately 2% in European-descent patients and can reach frequencies of up to 15-40% in PD Ashkenazi Jews and North African Arabs.

Significance of the second peak of systolic blood pressure for identifying both high and low cardiovascular risk states.

This study was conducted to clarify whether the second peak of the systolic blood pressure (SBP2) has significant information about cardiovascular (CV) risk state, independent of the brachial BP. SBP2 was measured by radial pressure wave analysis in 7847 Japanese subjects (50+/-10 years old), and the Framingham risk score (FRS) and general cardiovascular disease risk score were calculated (FRSgen). The results of multivariate analysis revealed that the SBP2 showed a significant correlation with the FRS (beta=0.

Effects of CPAP therapy on the sympathovagal balance and arterial stiffness in obstructive sleep apnea.

Objective: Increased arterial stiffness and sympathovagal imbalance are noted in patients with obstructive sleep apnea (OSA). It has been thought that continuous positive airway pressure (CPAP) therapy can have beneficial effects on the vascular function in such cases. However, it is not yet clear whether the improvement of sympathovagal balance by CPAP might be related to reduction of the arterial stiffness, independent of changes in the blood pressure.

Relationship of insulin resistance to macro- and microvasculature reactivity in hypertension.

Background: Although insulin resistance (IR) is thought to be related to vascular dysfunction, the difference in the relationship of IR to microvasculature and macrovasculature reactivity has not yet been clarified. The present study was conducted to clarify whether the IR is more closely related to the macrovasculature reactivity (flow-mediated vasodilatation of the brachial artery induced by reactive hyperemia: FMD) or microvasculature reactivity (skin reactive hyperemia as assessed by laser Doppler flowmetry: SRH) in patients with hypertension.

Methods: In 75 consecutive hypertensive patients (61 +/- 11 years of age) without obvious cardiovascular (CV) disease and/or risk factors for CV disease other than hypertension, FMD, SRH, and homeostasis model assessment index of IR (HOMA(IR)) were measured.

Synergistic relationship between changes in the pulse wave velocity and changes in the heart rate in middle-aged Japanese adults: a prospective study.

Objectives: Temporal associations between rates of increases in pulse wave velocity (PWV), a marker of arterial stiffness, and heart rate (HR) indices (baseline HR and changes in HR) as well as inflammatory markers were examined.

Methods: In 1795 apparently healthy Japanese individuals (mean age 39 +/- 8 years old), brachial-ankle PWV (baPWV) and serum C-reactive protein (CRP) levels were measured at the baseline and at the end of a 5-6-year follow-up period.

Results: Heart rate at the baseline examination and changes in HR during the follow-up period were significantly associated with the corresponding changes in baPWV during the study period (nonstandardized co-efficient = 0.

A large-scale genetic association study to evaluate the contribution of Omi/HtrA2 (PARK13) to Parkinson's disease.

High-profile studies have provided conflicting results regarding the involvement of the Omi/HtrA2 gene in Parkinson's disease (PD) susceptibility. Therefore, we performed a large-scale analysis of the association of common Omi/HtrA2 variants in the Genetic Epidemiology of Parkinson's disease (GEO-PD) consortium. GEO-PD sites provided clinical and genetic data including affection status, gender, ethnicity, age at study, age at examination (all subjects); age at onset and family history of PD (patients).

Non-invasive vascular function tests: their pathophysiological background and clinical application.

The arterial wall has 3 layers (ie, the intima, including the endothelium, the media, and the adventitia); each of these layers has individual roles in systemic circulation. The vascular endothelium regulates the vascular tone, hemostasis and/or vascular permeability, and the media is the major determinant of arterial elasticity, which regulates the conduit function (delivery of blood to tissues) and cushioning effect (for generation of continuous blood flow). Failure of these functions results in organ/vascular damage.

Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease.

To identify susceptibility variants for Parkinson's disease (PD), we performed a genome-wide association study (GWAS) and two replication studies in a total of 2,011 cases and 18,381 controls from Japan. We identified a new susceptibility locus on 1q32 (P = 1.52 x 10(-12)) and designated this as PARK16, and we also identified BST1 on 4p15 as a second new risk locus (P = 3.