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A heterozygous loss-of-function variant in lin-28 homolog A (LIN28A) was recently reported as a novel pathogenic gene in patients with PD from Korea. Two patients harboring LIN28Avariants had early- or middle-aged-onset PD with good responses to levodopa. In the current study, we aimed to identify the prevalence of LIN28Avariants among PD patients of Japanese origin. We performed genetic sequencing of 284 patients with early-onset PD. We then estimated the frequency and functional effect of each variant using prediction tools. We identified three different rare variants in LIN28A(rs4623750, c.228 + 49 C > T; rs199541048, c.*7 A > G; and rs4659441, c.*43 C > T). The frequency of each variant in the PD patients did not differ from that of the general population. No variants were identified in the amino acid-coding regions. Our results do not support a strong association of LIN28Awith early-onset PD among Japanese patients.

Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson’s disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). We found a significant inverse association between smoking initiation and PD (ORIVWper 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60–0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

Parkinson’s disease (PD) is a neurodegenerative disorder primarily characterized by motor dysfunction. Aging is the greatest risk factor for developing PD. Recent molecular genetic studies have revealed that genetic factors, in addition to aging and environmental factors, play an important role in the development of the disorder. Studies of familial PD have identified approximately 20 different causative genes. PRKNis the most frequently detected causative gene in Japan. The PRKNgene is located at a common fragile site, and both copy number variants as well as single nucleotide variants are frequently detected. The location and variety of variant types makes an accurate genetic diagnosis difficult with conventional genetic testing. In sporadic PD, genome-wide association studies have revealed more than 200 genes that are potential drivers for the development of PD. Many of these studies have been conducted in Caucasian populations alone, which has limited the identification of all genetic risk factors for sporadic PD, particularly as genetic backgrounds vary widely by race. The Global Parkinson’s Genetics Program is a global undertaking meant to address the issue of regional differences in genetic studies of PD.

To clarify the significance of newly appearing abnormal Q waves and their disappearance in patients with Kawasaki disease, regional myocardial perfusion and glucose metabolism at rest in the fasting condition were assessed by positron emission tomography (PET) with [.sup.13]N-ammonia and [.sup.18]F-fluorodeoxyglucose (FDG), and regional wall motion by left ventriculography in regions with persistent and transient abnormal Q waves in 14 patients. PET identified 3 groups of abnormal myocardial segments: segments with hypoperfusion without increased FDG uptake, those with hypoperfusion and increased FDG uptake, and those with normal perfusion and increased FDG uptake. Almost all the segments with persistent or transient abnormal Q waves had abnormal PET findings. PET demonstrated evidence of metabolic activity in 57% of segments with persistent abnormal Q waves and 67% of those with transient abnormal Q waves. Regional wall motion, scored from 0 (normal) to 4 (dyskinesia), was not significantly different between segments with persistent and transient abnormal Q waves (2.3 [+ or -] 1.3 vs. 2.2 [+ or -] 1.2). The persistence of abnormal Q waves on serial electrocardiograms was significantly shorter in metabolically active in inactive segments (19 [+ or -] 17 vs 92 [+ or -] 27 months). In conclusion, in patients with Kawasaki disease, the new appearance of abnormal Q waves is a reliable clue to the presence of ischemic myocardial injury and a high proportion of them are associated with metabolically active myocardial regions. The disappearance of abnormal Q waves does not necessarily mean the normalization of regional myocardial perfusion, metabolism or function, and their early disappearance may imply 'viability' in the associated myocardial region. (Am J Cardiol 1991;68:1638-1645)

Variants of leucine-rich repeat kinase 2(LRRK2) are the most common genetic cause of familial Parkinson’s disease (PD). We aimed to investigate the genetic and clinical features of patients with PD and LRRK2variants in Japan by screening for LRRK2variants in three exons (31, 41, and 48), which include the following pathogenic mutations: p.R1441C, p.R1441G, p.R1441H, p.G2019S, and p.I2020T. Herein, we obtained data containing LRRK2variants derived from 1402 patients with PD (653 with sporadic PD and 749 with familial PD). As a result, we successfully detected pathogenic variants (four with p.R1441G, five with p.R1441H, seven with p.G2019S, and seven with p.I2020T) and other rare variants (two with p.V1447M, one with p.V1450I, one with p.T1491delT, and one with p.H2391Q). Two risk variants, p.P1446L and p.G2385R, were found in 10 and 146 patients, respectively. Most of the patients presented the symptoms resembling a common type of PD, such as middle-aged onset, tremor, akinesia, rigidity, and gait disturbance. Dysautonomia, cognitive decline, and psychosis were rarely observed. Each known pathogenic variant had a different founder in our cohort proven by haplotype analysis. The generation study revealed that the LRRK2variants p.G2019S and p.I2020T were derived 3500 and 1300 years ago, respectively. Our findings present overviews of the prevalence and distribution of LRRK2variants in Japanese cohorts.

Individuals with hereditary spastic paraplegia (HSP) are known to present with a variety of symptoms, including intellectual disability, cognitive decline, parkinsonism, and epilepsy. We report here our experience of treating a family with consanguinity, including three patients with HSP-related symptoms. We performed whole-exome sequencing and identified a novel pathogenic nonsense variant, c.4544G > A, p.W1515*, in the SPG11gene. Proband and her affected sister showed the same course of gait disturbance due to spastic paraplegia from childhood and progressive cognitive decline from early adulthood. Brain MRI depicted a thinning of the corpus callosum, severe atrophic changes in the frontotemporal lobes, and ears of the lynx sign. Patients with SPG11variants clinically present with distinctive symptoms.

OBJECTIVE To determine the association of the genes that encode α-, β-, and γ-synuclein (SNCA, SNCB, and SNCG, respectively) with diffuse Lewy body disease (DLBD). DESIGN Case-control study. SUBJECTS A total of 172 patients with DLBD consistent with a clinical diagnosis of Parkinson disease dementia/dementia with Lewy bodies and 350 clinically and 97 pathologically normal controls. INTERVENTIONS Sequencing of SNCA, SNCB, and SNCG and genotyping of single-nucleotide polymorphisms performed on an Applied Biosystems capillary sequencer and a Sequenom MassArray pLEX platform, respectively. Associations were determined using χ2 or Fisher exact tests. RESULTS Initial sequencing studies of the coding regions of each gene in 89 patients with DLBD did not detect any pathogenic substitutions. Nevertheless, genotyping of known polymorphic variability in sequence-conserved regions detected several single-nucleotide polymorphisms in the SNCA and SNCG genes that were significantly associated with disease (P = .05 to <.001). Significant association was also observed for 3 single-nucleotide polymorphisms located in SNCB when comparing DLBD cases and pathologically confirmed normal controls (P = .03-.01); however, this association was not significant for the clinical controls alone or the combined clinical and pathological controls (P > .05). After correction for multiple testing, only 1 single-nucleotide polymorphism in SNCG (rs3750823) remained significant in all of the analyses (P = .05-.009). CONCLUSION These findings suggest that variants in all 3 members of the synuclein gene family, particularly SNCA and SNCG, affect the risk of developing DLBD and warrant further investigation in larger, pathologically defined data sets as well as clinically diagnosed Parkinson disease/dementia with Lewy bodies case-control series.Arch Neurol. 2010;67(8):970-975--

Pain is one of the common symptoms in patients with Parkinson's disease (PD), with a prevalence of approximately 40–85%. These symptoms affect the quality of life of PDpatients. We evaluated the effect of spinal cord stimulation (SCS) to chronic pain and motor symptoms of PD. Three PDpatients were treated with SCSto relieve their persistent and intractable pain. One patient had failed back surgery syndrome and the other two had lumbar canal stenosis. All patients had a stooped posture and pain that was resistant to analgesics. We evaluated motor symptoms using Hoehn and Yahr scale and the Unified Parkinson's Disease Rating Scale (UPDRS), and evaluated pain using visual analog scale and widespread pain index, before and after SCS. After SCSinsertion, chronic pain in the patients decreased in both the lower back and limbs. Moreover, SCSameliorated the symptoms of PD. One‐year follow‐up after SCSshowed that UPDRSpart IIIscores, rigidity, and tremor were improved without large alterations in levodopa dosage. Dementia and activities of daily living did not improve after SCS. Our results indicate that SCSmay be a treatment option for both motor symptoms and chronic pain in PD, especially in cases complicated with lumbar canal stenosis or disc herniation. Further studies are needed to evaluate the efficacy of SCSin PDpatients.

Recently, genomic multiplications of α‐synuclein gene (SNCA) have been reported to cause hereditary early‐onset parkinsonism. The objective of this study was to assess the frequency of SNCA multiplications among autosomal dominant hereditary Parkinson's disease (ADPD). We screened 113 ADPD probands and 200 sporadic PD cases by quantitative polymerase chain reaction and confirmed SNCAmultiplications by flurorescence in situ hybridization (FISH) and comparative genomic hybridization array. Two families (two patients from Family A and one from Family B) with SNCA duplication were identified among ADPD patients. Even though they had the same SNCAduplication, one patient had dementia. Because there was exactly the same difference between the regions originated from each patient, the finding suggests that the phenotype of SNCAmultiplication may be also influenced by the range of duplication region. We also detected asymptomatic carriers in the families of both patients. Interestingly, the penetrance ratio was 33.3% (2/6) in one kindred, indicating that the ratio was very much lower than expected. These two newly identified Japanese patients with SNCAduplication and the five previously identified American and European families with SNCAtriplication or duplication mutations indicate that the incidence of SNCAmultiplication may be more frequent than previously estimated. Ann Neurol 2006

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This study was conducted to investigate myocardial excitation-contraction coupling in the fetus of the diabetic rabbit (FDM). On day 14 of gestation, diabetes was induced in pregnant rabbits by alloxan injection. On day 28 of gestation, mechanical function of the fetal myocardium was determined in the isolated arterially perfused heart preparation. At 1.5 mM Ca2o(control), the force of myocardial contraction in FDM was not significantly dfferent from that in the control fetus. At higher Ca2o, developed tension and maximal rate of tension development dT/dt (max) in FDM were significantly greater than in the control fetus. High Ca2ocaused significant increases in resting tension and half-relaxation time (toxic effects) in the control fetus, but not in FDM. Perfusion with lanthanum (known to displace sarcolemma-bound Ca2and block sarcolemmal Na-Ca exchange) decreased developed tension and dT/dt (max) and increased resting tension and these effects in FDM were significantly less than in the control fetus. Perfusion with manganese (known to displace Ca2from intracellular sites) also decreased developed tension and dT/dt (max) and increased resting tension, and these effects were similar in the two groups. The myofibrillar ATPase activities at various calcium concentrations were not different between the two groups. The rates of Ca2uptake by mitochondria and sarcoplasmic reticulum were similar in the two groups. These data suggest that in FDM the inotropic effect of Ca2is greater and the toxic effect of Ca2is less than in the control fetus. This difference may be due, at least in part, to a sarcolemmal alteration induced by the maternal diabetes.

Myocardial mitochondrial function after acute adriamycin exposure was compared in infant and adult mice. Heart mitochondria were isolated 48 h after an intraperitoneal injection of adriamycin. Concentrations of adriamycin in serum and heart tissue were not significantly different between infant and adult mice. Oxygen consumption (state 3 respiration), and respiratory control ratio (RCR) were studied polarographically. Enzyme activities in the respiratory chain [succinate-cytochrome c reductase (SCCR), NADH-cytochrome c reductase (NCCR), cytochrome c oxidase (CCO)], and adenine nucleotide translocase (ANT) were assayed. After saline injection (control), no significant differences were detected in state 3 respiration, RCR, and enzyme activity of ANT between infant and adult mice. The respective enzyme activities of SCCR, NCCR, and CCO in adult mice were significantly lower than those in infant mice. After adriamycin injection in adult mice, there were significant decreases in state 3 respiration (using glutamate and malate as substrates from 239 ± 25 to 160 ± 50 nanoatom O2/min/mg protein), RCR (using glutamate and malate as substrates from 7.2 ± 1.0 to 4.4 ± 1.4), and enzyme activities of SCCR (from 279 ± 30 to 178 ± 28 nmol/min/mg protein) and NCCR (from 331 ± 43 to 237 ± 30 nmol/min/mg protein), but there were no significant changes in infant mice. No significant changes in enzyme activities of CCO and ANT were found in either infant or adult mice following the administration of adriamycin. In conclusion, adriamycin is less toxic on the myocardial mitochondrial function in infant mice than in adult mice.

Yoshibayashi M, Kamiya T. Saito Y. Nakao K, Nishioka K, Temma S, Itoh H, Shirakami G, Matsuo H. Plasma brain natriuretic peptide concentrations in healthy children from birth to adolescence: marked and rapid increase after birth. Eur J Endocrinol 1995;133:207–9. ISSN 0804–4643The aim of the present study is to establish the normal range and to determine the developmental changes of plasma brain natriuretic peptide (BNP) concentrations in children. We measured plasma BNP concentrations as well as atrial natriuretic peptide (ANP) concentrations in 58 healthy children from birth to adolescence and in the umbilical vein of 20 healthy neonates using highly sensitive immunoradiometric assays. The plasma BNP concentration was the highest at 0 days of age and descended through maturation to be almost constant and to be at the adult level at 3 months of age. The plasma BNP concentration at 0 days of age (56.7 ± 49.6 fmol/ml; mean±sd) was 25 to 30 times higher than the adult level and 21 times higher than that in the umbilical vein (2.7 ± 1.4fmol/ml), The plasma ANP concentration at 0 days of age was not significantly different from that in the umbilical vein. The ratio of BNP to ANP was also the highest at 0 days of age (1.39 ± 0.72) and decreased through maturation to be at the adult level at 3 months of age. Thus, the plasma BNP concentration in healthy subjects showed a marked, rapid and preferential increase immediately after birth, suggesting that BNP has a physiological role distinct from that of ANP in the perinatal circulatory changes from fetus to neonate.Muneo Yoshibayashi, Department of Pediatrics, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565, Japan

The aim of this study was to investigate vulnerability and long-term influence of traumatic stress caused by the Great East Japan Disaster which occurred on March 11, 2011, in patients with fibromyalgia, which is a chronic pain syndrome probably involving central sensitization.