Mitochondrial (mt) impairment, particularly within complex I of the electron transport system, has been implicated in the pathogenesis of Parkinson disease (PD). More than half of mitochondrially ...encoded polypeptides form part of the reduced nicotinamide adenine dinucleotide dehydrogenase (NADH) complex I enzyme. To test the hypothesis that mtDNA variation contributes to PD expression, we genotyped 10 single-nucleotide polymorphisms (SNPs) that define the European mtDNA haplogroups in 609 white patients with PD and 340 unaffected white control subjects. Overall, individuals classified as haplogroup J (odds ratio OR 0.55; 95% confidence interval CI 0.34–0.91; P=.02) or K (OR 0.52; 95% CI 0.30–0.90; P=.02) demonstrated a significant decrease in risk of PD versus individuals carrying the most common haplogroup, H. Furthermore, a specific SNP that defines these two haplogroups, 10398G, is strongly associated with this protective effect (OR 0.53; 95% CI 0.39–0.73; P=.0001). SNP 10398G causes a nonconservative amino acid change from threonine to alanine within the NADH dehydrogenase 3 (ND3) of complex I. After stratification by sex, this decrease in risk appeared stronger in women than in men (OR 0.43; 95% CI 0.27–0.71; P=.0009). In addition, SNP 9055A of ATP6 demonstrated a protective effect for women (OR 0.45; 95% CI 0.22–0.93; P=.03). Our results suggest that ND3 is an important factor in PD susceptibility among white individuals and could help explain the role of complex I in PD expression.
CONTEXT The relative contribution of
genes
vs environment in idiopathic Parkinson
disease (PD) is controversial. Although genetic studies have identified 2
genes in which
mutations cause rare ...single-gene variants of PD and observational
studies have suggested a genetic component, twin studies have suggested that
little genetic contribution exists in the common forms of PD. OBJECTIVE To identify genetic risk factors for idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS Genetic
linkage study conducted 1995-2000 in which a complete
genomic screen (n = 344 markers) was performed in 174 families with multiple individuals
diagnosed as having idiopathic PD, identified through probands in 13 clinic
populations in the continental United States and Australia. A total of 870
family members were studied: 378 diagnosed as having PD, 379 unaffected by
PD, and 113 with unclear status. MAIN OUTCOME MEASURES Logarithm of odds (lod) scores generated from
parametric and nonparametric genetic linkage analysis. RESULTS Two-point parametric maximum parametric lod score (MLOD) and multipoint
nonparametric lod score (LOD) linkage analysis detected significant evidence
for linkage to 5 distinct chromosomal regions:
chromosome 6 in the parkin
gene (MLOD = 5.07; LOD = 5.47) in families with at least 1 individual with
PD onset at younger than 40 years, chromosomes 17q (MLOD = 2.28; LOD = 2.62),
8p (MLOD = 2.01; LOD = 2.22), and 5q (MLOD = 2.39; LOD = 1.50) overall and
in families with late-onset PD, and chromosome 9q (MLOD = 1.52; LOD = 2.59)
in families with both levodopa-responsive and levodopa-nonresponsive patients. CONCLUSIONS Our data suggest that the parkin gene is important in early-onset PD
and that multiple genetic factors may be important in the development of idiopathic
late-onset PD.
Methane (CH4) effluxes by paddy-culture rice (Oryza sativa L.) contribute about 16% of the total anthropogenic emissions. Since radiative forcing of CH4 at current atmospheric concentrations is 21 ...times greater on a per mole basis than that of carbon dioxide (CO2),it is imperative that the impact of global change on rice CH4 emissions be evaluated. Rice (cv.IR72) was planted in sunlit, closed-circulation, controlled-environment chambers in which CH4 efflux densities were measured daily. The CO2 concentration was maintained at either 330 or 660 micromol mol-1. Air temperatures were controlled to daily maxima and minima of 32/23,35/26, and 38/29 degrees C at each CO2 treatment. Emissions of CH4 each day were determined during a 4-h period after venting and resealing the chambers at 0800 h. Diurnal CH4 effluxes on 77, 98, and 119 d after planting (DAP) were obtained similarly at 4-h intervals. Emissions over four-plant hills and over flooded bare soil were measured at 53, 63, and 100 DAP. Emissions were negligible before 40 DAP. Thereafter, emissions were observed first in high CO2, high-temperature treatments and reached a sustained maximum efflux density of about 7 mg m-2 h-1 (0.17 g m-2 d-1) near the end of the growing season. Total seasonal CH4 emission was fourfold greater for high-CO2, high-temperature treatments than for the low CO2, low-temperature treatment, probably due to more root sloughing or exudates, since about sixfold more acetate was found in the soil at 71 DAP. Both rising CO2 and increasing temperatures could lead to a positive feedback on global warming by increasing the emissions of CH4 from rice.
The physiological state of the cell is controlled by signal transduction mechanisms which regulate the balance between protein kinase and protein phosphatase activities. Here we report that a single ...protein can, depending on which particular amino-acid residue is phosphorylated, function either as a kinase or phosphatase inhibitor. DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34 (refs 2, 3). We find that DARPP-32 is converted into an inhibitor of PKA when phosphorylated at threonine 75 by cyclin-dependent kinase 5 (Cdk5). Cdk5 phosphorylates DARPP-32 in vitro and in intact brain cells. Phospho-Thr 75 DARPP-32 inhibits PKA in vitro by a competitive mechanism. Decreasing phospho-Thr 75 DARPP-32 in striatal slices, either by a Cdk5-specific inhibitor or by using genetically altered mice, results in increased dopamine-induced phosphorylation of PKA substrates and augmented peak voltage-gated calcium currents. Thus DARPP-32 is a bifunctional signal transduction molecule which, by distinct mechanisms, controls a serine/threonine kinase and a serine/threonine phosphatase.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose We determined the efficacy and safety of pelvic floor myofascial physical therapy compared to global therapeutic massage in women with newly symptomatic interstitial cystitis/painful bladder ...syndrome. Materials and Methods A randomized controlled trial of 10 scheduled treatments of myofascial physical therapy vs global therapeutic massage was performed at 11 clinical centers in North America. We recruited women with interstitial cystitis/painful bladder syndrome with demonstrable pelvic floor tenderness on physical examination and a limitation of no more than 3 years' symptom duration. The primary outcome was the proportion of responders defined as moderately improved or markedly improved in overall symptoms compared to baseline on a 7-point global response assessment scale. Secondary outcomes included ratings for pain, urgency and frequency, the O'Leary-Sant IC Symptom and Problem Index, and reports of adverse events. We compared response rates between treatment arms using the exact conditional version of the Mantel-Haenszel test to control for clustering by clinical center. For secondary efficacy outcomes cross-sectional descriptive statistics and changes from baseline were calculated. Results A total of 81 women randomized to the 2 treatment groups had similar symptoms at baseline. The global response assessment response rate was 26% in the global therapeutic massage group and 59% in the myofascial physical therapy group (p = 0.0012). Pain, urgency and frequency ratings, and O'Leary-Sant IC Symptom and Problem Index decreased in both groups during followup, and were not significantly different between the groups. Pain was the most common adverse event, occurring at similar rates in both groups. No serious adverse events were reported. Conclusions A significantly higher proportion of women with interstitial cystitis/painful bladder syndrome responded to treatment with myofascial physical therapy than to global therapeutic massage. Myofascial physical therapy may be a beneficial therapy in women with this syndrome.
: Some cases of autosomal dominant familial amyotrophic lateral sclerosis (FALS) are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1), suggesting that oxidative damage ...may play a role in ALS pathogenesis. To further investigate the biochemical features of FALS and sporadic ALS (SALS), we examined markers of oxidative damage to protein, lipids, and DNA in motor cortex (Brodmann area 4), parietal cortex (Brodmann area 40), and cerebellum from control subjects, FALS patients with and without known SOD mutations, SALS patients, and disease controls (Pick's disease, progressive supranuclear palsy, diffuse Lewy body disease). Protein carbonyl and nuclear DNA 8‐hydroxy‐2′‐deoxyguanosine (OH8dG) levels were increased in SALS motor cortex but not in FALS patients. Malondialdehyde levels showed no significant changes. Immunohistochemical studies showed increased neuronal staining for hemeoxygenase‐1, malondialdehyde‐modified protein, and OH8dG in both SALS and FALS spinal cord. These studies therefore provide further evidence that oxidative damage may play a role in the pathogenesis of neuronal degeneration in both SALS and FALS.
CONTEXT The human tau gene, which promotes assembly of neuronal microtubules,
has been associated with several rare neurologic diseases that clinically
include parkinsonian features. We recently ...observed
linkage in idiopathic
Parkinson disease (PD) to a region on
chromosome 17q21 that contains the tau
gene. These factors make tau a good candidate for investigation as a susceptibility
gene for idiopathic PD, the most common form of the disease. OBJECTIVE To investigate whether the tau gene is involved in idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS Among a sample of 1056 individuals from 235 families selected from 13
clinical centers in the United States and Australia and from a family ascertainment
core center, we tested 5
single-nucleotide polymorphisms (SNPs) within the
tau gene for association with PD, using family-based tests of association.
Both affected (n = 426) and unaffected (n = 579) family members were included;
51 individuals had unclear PD status. Analyses were conducted to test individual
SNPs and SNP haplotypes within the tau gene. MAIN OUTCOME MEASURE Family-based tests of association, calculated using asymptotic distributions. RESULTS Analysis of association between the SNPs and PD yielded significant
evidence of association for 3 of the 5 SNPs tested: SNP 3, P = .03; SNP 9i, P = .04; and SNP 11, P = .04. The 2 other SNPs did not show evidence of significant
association (SNP 9ii, P = .11, and SNP 9iii, P = .87). Strong evidence of association was found with
haplotype analysis, with a positive association with one haplotype (P = .009) and a negative association with another haplotype
(P = .007). Substantial linkage disequilibrium (P<.001) was detected between 4 of the 5 SNPs (SNPs 3,
9i, 9ii, and 11). CONCLUSIONS This integrated approach of genetic linkage and positional association
analyses implicates tau as a susceptibility gene for idiopathic PD.
To identify genes influencing age at onset (AAO) in two common neurodegenerative diseases, a genomic screen was performed for AAO in families with Alzheimer disease (AD;
n=449) and Parkinson disease ...(PD;
n=174). Heritabilities between 40%–60% were found in both the AD and PD data sets. For PD, significant evidence for linkage to AAO was found on chromosome 1p (LOD = 3.41). For AD, the AAO effect of APOE (LOD = 3.28) was confirmed. In addition, evidence for AAO linkage on chromosomes 6 and 10 was identified independently in both the AD and PD data sets. Subsequent unified analyses of these regions identified a single peak on chromosome 10q between D10S1239 and D10S1237, with a maximum LOD score of 2.62. These data suggest that a common gene affects AAO in these two common complex neurodegenerative diseases.
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