BACKGROUND:: Parkinson disease (PD) is associated with a progressive decline in patient quality of life (QoL), because of motor and nonmotor manifestations of PD and treatment-related side effects. REVIEW SUMMARY:: Treatment with carbidopa/levodopa-the current gold standard therapy-improves QoL in the short term, but gains are not maintained over a long term. Long-term treatment is associated with symptom re-emergence (end-of-dose "wearing off") and development of dyskinesia, which may have an adverse impact on QoL. CONCLUSIONS:: Levodopa (LD; combined with carbidopa) remains the gold standard for symptomatic treatment of PD, but long-term treatment is associated with complications that may adversely affect QoL. Recent studies have suggested that the addition of a catechol-O-methyltransferase inhibitor may improve QoL through the reduction of some of the motor complications of LD therapy. Further studies are required to determine the full effects of this as well as other treatments that are used to manage LD-associated complications on QoL.

OBJECTIVE: To evaluate the relative importance of smoking duration vs intensity in reducing the risk of Parkinson disease (PD). METHODS: The study included 305,468 participants of the NIH-AARP Diet and Health cohort, of whom 1,662 had a PD diagnosis after 1995. We estimated odds ratios (OR) and 95% confidence intervals from multivariate logistic regression models. RESULTS: Compared with never smokers, the multivariate ORs were 0.78 for past smokers and 0.56 for current smokers. Among past smokers, a monotonic trend toward lower PD risk was observed for all indicators of more smoking. Stratified analyses indicated that smoking duration was associated with lower PD risk within fixed intensities of smoking. For example, compared with never smokers, the ORs among past smokers who smoked >20 cigarettes/day were 0.96 for 1-9 years of smoking, 0.78 for 10-19 years, 0.64 for 20-29 years, and 0.59 for 30 years or more (p for trend = 0.001). In contrast, at fixed duration, the typical number of cigarettes smoked per day in general was not related to PD risk. Close examination of smoking behaviors in early life showed that patients with PD were less likely to be smokers at each age period, but if they smoked, they smoked similar numbers of cigarettes per day as individuals without PD. CONCLUSIONS: This large study suggests that long-term smoking is more important than smoking intensity in the smoking-Parkinson disease relationship.

OBJECTIVE: To clinically characterize the temporal relationship between dyskinesia and the antiparkinsonian response when dyskinesia first emerges during long-term levodopa therapy and to determine if it is consistent with the hypothesized mechanism by which dyskinesia develops. METHODS: Dyskinesia and the antiparkinsonian response to levodopa during 2-hour levodopa infusions were monitored at intervals through the first 4 years of long-term levodopa therapy in 20 subjects with idiopathic Parkinson disease (PD) and previously untreated with levodopa. The onset and offset of the antiparkinsonian response and dyskinesia were compared when dyskinesia first appeared during the 4 years. The findings were compared to 20 subjects with PD on longterm levodopa with dyskinesia and motor fluctuations. RESULTS: The onset and offset of the antiparkinsonian response and dyskinesia generally coincided when dyskinesia first appeared during the 4 years and did not suggest any temporal dissociation of the 2 responses. Further, the latency to the onsets of dyskinesia and the antiparkinsonian response tended to shorten during long-term levodopa therapy, suggesting that both responses were sensitized by long-term levodopa. CONCLUSIONS: The similar onsets and offsets of the antiparkinsonian response and dyskinesia when dyskinesia first appears are not consistent with the postulated progressive decrease in threshold for dyskinesia during long-term levodopa therapy. Other mechanisms for the development of dyskinesia need to be considered.

OBJECTIVES: We sought to determine concentrations of total and labile iron in substantia nigra from patients with Parkinson disease and from controls to assess if oxidative stress is triggered by an increased concentration of iron. METHODS: Total iron concentration in the whole substantia nigra was evaluated in 17 parkinsonian and 29 control samples. Concentrations of labile iron and copper were assessed in 6 parkinsonian and 8 control samples. The total iron concentration, the Fe(2+)/Fe(3+) ratio, and iron-binding compounds were determined by Mössbauer spectroscopy. Labile iron and copper were measured by electrothermal atomic absorption spectrometry. Activity of reactive oxygen species was evaluated by visible light fluorescence. RESULTS: The labile iron concentration was significantly higher and corresponded to significantly higher reactive oxygen species activity in parkinsonian vs control samples. No significant difference was found in the total concentrations of copper or iron in the whole substantia nigra between parkinsonian and control samples. Mössbauer spectroscopy detected no Fe(2+) in any samples. CONCLUSIONS: The substantia nigra of parkinsonian patients contained more labile iron compared with that of controls. This labile iron generated higher reactive oxygen species activity. The oxidative stress damage in parkinsonian substantia nigra may be related to an excess of labile iron and not of the total iron in the diseased tissue.

OBJECTIVES:: The aims of the present study were to investigate the pharmacokinetic and pharmacodynamic (pk/pd) relationship of levodopa (l-dopa) in patients with advanced Parkinson disease (PD) and also to evaluate the effect of tolcapone on the pk/pd analysis of l-dopa in 1 patient with severe dyskinesias and fluctuations. METHODS:: The pharmacokinetics (plasma concentrations of l-dopa and 3-O-methyldopa [3-OMD]) and motor effects (global score of the Unified Parkinson's Disease Rating Scale-III) of a single dose of l-dopa (plus the peripheral decarboxylase inhibitor 1:4) were determined in 14 patients with advanced PD. Patients were classified into 2 groups according to Hoehn and Yahr scale (stages 2 and 3). In 1 patient with severe dyskinesias and fluctuations, pk/pd of l-dopa were evaluated before and after coadministration of tolcapone at 100 mg 2 times daily for 1 month. The pk/pd analysis was based on an estimate of the maximal response model with a semiparametric approach to effect site equilibrium. RESULTS:: The highest levels of l-dopa and 3-OMD were observed in patients with stage 3 of Hoehn and Yahr scale. We showed differences in the pk/pd parameters after coadministration of tolcapone in 1 patient as well as the clinical improvement.Univariate analysis showed some significant correlations (P < 0.05) between l-dopa pk/pd parameters and patients' age, duration of l-dopa treatment, and duration of the disease. Multivariate analysis adjusted for patients' age, sex, duration of the disease, and Hoehn and Yahr stage showed that presence of diphasic (dyskinesia-improvement-dyskinesia [DID]) dyskinesias was the only independent predictor of larger threshold level - EC50 (mean concentration at half maximal effect) of l-dopa (P = 0.034). CONCLUSIONS:: The motor complications during long treatment therapy in patients with advanced PD especially with stage 3 Hoehn and Yahr scale were correlated to the higher plasma concentrations of l-dopa. In the presented study, patients with motor complications, especially with DID dyskinesias, exhibited a larger threshold level (EC50). The clinical improvement of a patient who received l-dopa and tolcapone can be explained by tolcapone-induced changes of peripheral and central l-dopa pharmacokinetics, which led to a decrease of l-dopa EC50 and 3-OMD concentrations. Our data indicate that pk/pd analysis may be helpful for monitoring the efficiency of therapeutic strategy applied in PD patients.

Gradients of nucleotide bias and substitution rates occur in vertebrate mitochondrial genomes due to the asymmetric nature of the replication process. The evolution of these gradients has previously been studied in detail in primates, but not in other vertebrate groups. From the primate study, the strengths of these gradients are known to evolve in ways that can substantially alter the substitution process, but it is unclear how rapidly they evolve over evolutionary time or how different they may be in different lineages or groups of vertebrates. Given the importance of mitochondrial genomes in phylogenetics and molecular evolutionary research, a better understanding of how asymmetric mitochondrial substitution gradients evolve would contribute key insights into how this gradient evolution may mislead evolutionary inferences, and how it may also be incorporated into new evolutionary models. Most snake mitochondrial genomes have an additional interesting feature, 2 nearly identical control regions, which vary among different species in the extent that they are used as origins of replication. Given the expanded sampling of complete snake genomes currently available, together with 2 additional snakes sequenced in this study, we reexamined gradient strength and CR usage in alethinophidian snakes as well as several lizards that possess dual CRs. Our results suggest that nucleotide substitution gradients (and corresponding nucleotide bias) and CR usage is highly labile over the approximately 200 m.y. of squamate evolution, and demonstrates greater overall variability than previously shown in primates. The evidence for the existence of such gradients, and their ability to evolve rapidly and converge among unrelated species suggests that gradient dynamics could easily mislead phylogenetic and molecular evolutionary inferences, and argues strongly that these dynamics should be incorporated into phylogenetic models.

Sleep in dementias has been mainly studied in Alzheimer disease (AD). Sleep disturbances are found in 25 to 35% of subjects with AD. Subjective and objective disturbances are described. Long nocturnal awakenings disrupt sleep; total sleep time and sleep efficiency are reduced. Slow wave sleep is decreased and sometimes disappears. REM sleep percentage is also reduced and at a later stage of the disease, REM latency is increased. Sleep fragmentation can be associated with excessive daytime napping and sleepiness, and with other behavioral symptoms such as the sundowning syndrome and nocturnal agitation. Sleep abnormalities closely parallel the level of severity of dementia. The rest/activity ratio and the sleep-wake rhythms are more and more disturbed; the phase delay of the temperature rhythm is associated with the severity of the sundowning syndrome. Sleep disturbances and behavioral symptoms are the main reasons to institutionalize the patient. Sleep disturbances are related to multiple factors. Pathophysiological changes resulting of the disease itself, such as damage to the cholinergic pathways and to the circadian pacemaker in the suprachiasmatic nucleus, contribute to sleep changes in AD. Associated medical and psychiatric illness and their different treatments as well as environmental factors also induced sleep disturbances. Sleep-disordered breathing is a highly prevalent condition in AD patients and restless leg syndrome may account for nocturnal agitation. In Parkinson and in Lewy body dementias, sleep disturbances are more severe than in DA and REM sleep behavior disorder can precede by several years these diseases. Sleep attacks and sleepiness are very frequent in Parkinson disease. Specific etiologies should drive specific treatment. Several non pharmacologic treatments are usually associated to treat sleep disturbances in AD: information, increased daytime physical, social activities to minimize daytime naps and exposure to bright light. Some studies found advantages to associate melatonin in the evening.

ABSTRACT: We present an extensible software model for the genotype and phenotype community, XGAP. Readers can download standard XGAP (www.xgap.org) or generate a custom version using MOLGENIS with programming interfaces to R-software and web-services or user interfaces for biologists. XGAP has simple load formats for any type of genotype, epigenotype, transcript, protein, metabolite or other phenotype data. Current functionality includes tools ranging from eQTL analysis in mouse to genome-wide association studies in humans.

BACKGROUND AND PURPOSE:: People with Parkinson's disease often have difficulty executing turns. To date, most studies of turning have examined subjects ON their anti-Parkinson medications. No studies have examined what specific aspects of turning are modified or remain unchanged when medication is administered. The purpose of this study was to determine how anti-Parkinson medications affect temporal and spatial features of turning performance in individuals with Parkinson's disease. METHODS:: We examined turning kinematics in 10 people with Parkinson's disease who were assessed both OFF and ON medication. For both conditions, participants were evaluated with the Unified Parkinson's Disease Rating Scale motor subscale, rated how well their medication was working on a visual analog scale, and performed straight-line walking and 180-degree in-place turns. We determined the average walking velocity, time and number of steps to execute turns, sequence of yaw rotation onsets of the head, trunk, and pelvis during turns, and amplitudes of yaw rotation of the head, trunk, and pelvis during turns. RESULTS:: Medication significantly improved the Unified Parkinson's Disease Rating Scale scores (P = 0.02), visual analog scale ratings (P = 0.03), and walking velocity (P = 0.02). Although improvements in turning were not statistically significant, medication did reduce the time and number of steps required to turn, slightly increased the amplitudes of yaw rotation of the various segments, and increased the rotation of the head relative to the other segments. Medication did not improve the timing of segment rotations, which showed en bloc turn initiation in both the OFF and ON medication conditions. DISCUSSION AND CONCLUSION:: These results suggest that only certain aspects of turning may be responsive to anti-Parkinson medications. As such, additional rehabilitative approaches to address turning are needed because turning may not be effectively addressed by pharmacologic approaches. These results should be interpreted cautiously given the small sample size.

OBJECTIVE: To evaluate the possible association of Parkinson disease (PD) and melanoma in North America. Design, Setting, and Patients Thirty-one centers enrolled patients with idiopathic PD. At visit 1, a neurologist obtained a medical history. At visit 2, a dermatologist recorded melanoma risk factors, performed a whole-body examination, and performed a biopsy of lesions suggestive of melanoma for evaluation by a central dermatopathology laboratory. We compared overall prevalence of melanoma with prevalence calculated from the US Surveillance Epidemiology and End Results (SEER) cancer database and the American Academy of Dermatology skin cancer screening programs. RESULTS: A total of 2106 patients (mean [SD] age, 68.6 [10.6] years; duration of PD, 7.1 [5.7] years) completed the study. Most (84.8%) had received levodopa. Dermatology examinations revealed 346 pigmented lesions; dermatopathological findings confirmed 20 in situ melanomas (0.9%) and 4 invasive melanomas (0.2%). In addition, histories revealed 68 prior melanomas (3.2%). Prevalence (5-year limited duration) of invasive malignant melanoma in the US cohort of patients with PD (n = 1692) was 2.24-fold higher (95% confidence interval, 1.21-4.17) than expected in age- and sex-matched populations in the US SEER database. Age- or sex-adjusted relative risk of any melanoma for US patients was more than 7 times that expected from confirmed cases in American Academy of Dermatology skin cancer screening programs. CONCLUSIONS: Melanoma prevalence appears to be higher in patients with PD than in the general population. Despite difficulties in comparing other databases with this study population, the study supports increased melanoma screening in patients with PD.

Parkinson's disease has been found to be caused by both, genetic and environmental factors. Despite the diversity of causes involved, a convergent pathogenic mechanism might underlie the special vulnerability of dopaminergic neurons in different forms of Parkinsonism. In recent years, a number of reports have proposed dopamine as a common player responsible in the loss of dopaminergic neurons independent of its etiology. Using RNAi lines we were able to generate flies with drastically reduced dopamine levels in the dopaminergic neurons. Combining these flies with a chemically induced Parkinson model (rotenone) and a familial form of Parkinson (mutant alpha-synuclein) we were able to show a strong reduction of neurotoxicity and a protection of the dopaminergic neurons when cellular dopamine levels were reduced. These results show that dopamine homeostasis plays a central role for the susceptibility of dopaminergic neurons to environmental and genetic factors in in vivo models of Parkinson disease.

Decrease in stratospheric ozone absorption and increase in oxygen absorption with decreasing wavelength combine to produce a window of maximum atmospheric transmission near 210 nm. Since solar radiation in this spectral region dissociates molecular oxygen, the deep atmospheric penetration at this wavelength is of particular aeronomical interest. High resolution calculations of the transmittance down to 28.65 km were made for the 200-243-nm spectral range in this window region, in support of a stratospheric balloon flight from Fort Churchill in July 1974. The calculations were made by dividing the atmosphere into layers which were chosen so that each could be assumed homogeneous; optical depths were calculated separatelyfor each of these layers and then summed to obtain the over-all transmittance of the atmosphere. Absorptionby molecular oxygen (line and continuum) and by ozone was included, as well as extinction through Rayleigh scattering by air molecules. The calculated transmittances were combined with hig h altitude(above 100-km) rocket measurements of the sun-center spectrum and center-to-limb variations to give residual high resolution solar spectral flux for several altitudes and solar zenith angles.

The ability of a drug to cause clinically significant drug-drug interactions due to direct or metabolism-dependent inhibition of cytochrome P450 (CYP) can generally be predicted from in vitro studies with human liver microsomes (HLM) or recombinant CYP enzymes, as recommended by the FDA and other regulatory agencies. This review highlights some examples of system-dependent inhibition of CYP and uridine diphosphate glucuronosyltransferase (UGT) enzymes. In the case of CYP enzymes, examples are presented where in vitro studies with HLM under-predict or over-predict the degree of inhibition observed in the clinic and where the correct prediction comes from studies with human hepatocytes. Studies with HLM under-predict the ability of gemfibrozil and bupropion to cause clinically significant inhibition of CYP2C8 and CYP2D6, respectively, and over-predict the ability of ezetimibe to cause clinically significant inhibition of CYP3A4. Gemfibrozil and bupropion represent examples of glucuronidation-dependent and reduction-dependent activation to metabolites that inhibit CYP2C8 and CYP2D6, respectively, whereas ezetimibe represents an example of glucuronidation-dependent protection against metabolism-dependent inhibition of CYP3A4. This article illustrates why, when drug candidates are extensively metabolized by non-CYP enzymes, it would be prudent to use human hepatocytes in addition to HLM or recombinant enzymes to evaluate their ability to inhibit CYP enzymes.

BACKGROUND: L-Threo-3,4-dihydroxyphenylserine (L-DOPS, droxidopa) is a norepinephrine (NE) prodrug under development to treat orthostatic hypotension. 3,4-Dihydroxyphenylacetaldehyde (DOPAL), an endogenous catecholaldehyde produced by enzymatic oxidative deamination of dopamine, is toxic to catecholaminergic neurons. Based on the observation of increasing plasma DOPAL after oral administration of L-DOPS to a patient, we examined whether other subjects also had DOPAL in their plasma after droxidopa administration, and whether droxidopa is contaminated with DOPAL. METHODS: Thirteen subjects took 400 mg droxidopa orally. We sampled venous blood at baseline and 1, 2, 3, 6, 24, and 48 h after drug administration and assayed L-DOPS, NE, and DOPAL by use of liquid chromatography with electrochemical detection (LC-ED). Droxidopa in acidic solution (20:80 mixture of 0.04 mol/L phosphoric acid:0.20 mol/L acetic acid) was vacuum centrifuged for 1 h at 30 degrees C and then assayed by LC-ED. RESULTS: Droxidopa contained 0.01% DOPAL. At 6 h after droxidopa, all subjects had detectable DOPAL in plasma (1.89 nmol/L, P = 0.0001). Across the sampling times, plasma DOPAL correlated with plasma L-DOPS (r = 0.996). The mean increment in plasma DOPAL was more than 4 times that in plasma NE (0.39 nmol/L). In 2 patients with Parkinson disease and orthostatic hypotension, DOPAL was detected in plasma at baseline (0.12 nmol/L) and increased by about 70-fold after droxidopa. Vacuum concentration of droxidopa in the acid solution converted L-DOPS to DOPAL completely. CONCLUSIONS: Droxidopa is contaminated with DOPAL. After oral droxidopa administration, DOPAL is detected in plasma of humans. Droxidopa is susceptible to extensive nonenzymatic conversion to DOPAL.

A case of Wolff-Parkinson-White syndrome with atrial fibrillation (AF) is reported in a patient who presented with syncope, tachycardia, and hypotension. The electrocardiogram (ECG) showed a fast irregular rhythm with wide polymorphic QRS tachycardia without the QRS twisting around the isoelectric baseline, diagnostic of AF and Wolff-Parkinson-White syndrome. The patient did not respond to intravenous amiodarone. Elective cardioversion restored sinus rhythm, and the ECG showed a wide QRS complex, short PR interval, and delta wave, indicating the presence of an accessory pathway and pre-excitation. AF was easily induced during the electrophysiologic study, requiring electrical cardioversion for severe hypotension. Successful radiofrequency ablation of the accessory pathway completely prevented further inducible AF. The patient no longer had any evidence of pre-excitation on ECG and remained symptom-free with no medications for 11 months.

Purpose. Dance may improve functional mobility in individuals with mild-to-moderate Parkinson disease (PD), yet dance effects in severe PD remain unexamined. This study's purpose was to evaluate the feasibility and effects of partnered tango classes on balance, endurance and quality of life in an individual with severe PD. Design. Over 10 weeks, the participant attended 20, 1-h tango classes for individuals with PD. Balance, walking, and quality of life were evaluated before and after the intervention and at a 1-month follow-up in this single case design. Caregiver burden was also assessed at all time points. Results. The participant improved on the Berg Balance Scale, 6-min walk test, and functional reach. He reported increased balance confidence and improved quality of life as measured by the Parkinson Disease Questionnaire-39 summary index. Gains were maintained at the 1-month follow-up. Caregiver burden increased from baseline immediately post-intervention and at follow-up. Conclusion. Twenty partnered tango lessons improved balance, endurance, balance confidence, and quality of life in a participant with severe PD. This is the first report of the use of dance as rehabilitation for an individual with advanced disease who primarily used a wheelchair for transportation.

The objective of the study was to characterize the natural history of patients with a higher level gait disorder (HLGD) of the cautious/disequilibrium type in a 3-year prospective study. Subjects were taken from an outpatient setting in a movement disorders clinic. Twenty-two mobile, community-living patients with a HLGD of the cautious/disequilibrium type and 26 age- and gender-matched healthy controls were evaluated at baseline and approximately 3 years later. Detailed medical history, a complete, structured geriatric and neurological examination, mental and affective state, gait and balance assessment were obtained. At follow-up, marked declines were observed in gait, mobility and functional independence in the patients, but not in the controls. For example, 23% of the patients could not complete the Timed Up and Go test, compared to only 4% of the control group, and among those who could complete the test, time to completion was almost three times longer (P < 0.0001) in the patients (23 s), compared to the controls (8 s). At follow-up, 50% of the patients required a personal live-in caregiver compared to only 4% of the controls (P < 0.0001). Although mild extra-pyramidal, pyramidal, cognitive and affective alterations were observed at baseline in the patients, those symptoms were stable over time. Unexpectedly, there was no association between the presence of HLGD or its progression and vascular risk factors. HLGD is a debilitating, rapidly progressive disease. The profound deterioration in functional independence in a relatively short period of time suggests that early multidisciplinary interventions may be the appropriate clinical approach to the treatment of these patients who are at risk for a rapid decline in functional abilities.

Concealment of an accessory pathway is caused by its ability to conduct retrogradely only. This variant of accessory pathway conduction could not be confirmed until invasive electrophysiology was introduced in the 1970s. As a rule, it is reported that concealed accessory pathways were predicted from animal experiments in 1971. However, even earlier studies suggested an accessory pathway or mechanisms comparable to those of the Wolff-Parkinson-White syndrome to be the cause of supraventricular tachycardias even though preexcitation during sinus rhythm had been lacking. Such interpretations were derived from clinical considerations, from patients having lost their ventricular preexcitation spontaneously, and from the disappearance of the delta wave after drug administration. Some authors postulated but did not provide the correct interpretation. Even a few contributions published before the paper of Wolff, Parkinson, and White in 1930 are worth considering in this context.

Increasing evidence suggests that phosphorylation may play an important role in the oligomerization, fibrillogenesis, Lewy body (LB) formation, and neurotoxicity of alpha-synuclein (alpha-syn) in Parkinson disease. Herein we demonstrate that alpha-syn is phosphorylated at S87 in vivo and within LBs. The levels of S87-P are increased in brains of transgenic (TG) models of synucleinopathies and human brains from Alzheimer disease (AD), LB disease (LBD), and multiple system atrophy (MSA) patients. Using antibodies against phosphorylated alpha-syn (S129-P and S87-P), a significant amount of immunoreactivity was detected in the membrane in the LBD, MSA, and AD cases but not in normal controls. In brain homogenates from diseased human brains and TG animals, the majority of S87-P alpha-syn was detected in the membrane fractions. A battery of biophysical methods were used to dissect the effect of S87 phosphorylation on the structure, aggregation, and membrane-binding properties of monomeric alpha-syn. These studies demonstrated that phosphorylation at S87 expands the structure of alpha-syn, increases its conformational flexibility, and blocks its fibrillization in vitro. Furthermore, phosphorylation at S87, but not S129, results in significant reduction of alpha-syn binding to membranes. Together, our findings provide novel mechanistic insight into the role of phosphorylation at S87 and S129 in the pathogenesis of synucleinopathies and potential roles of phosphorylation in alpha-syn normal biology.