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1.  Dilution of candidates: the case of iron-related genes in restless legs syndrome 
Restless legs syndrome (RLS) is a common multifactorial disease. Some genetic risk factors have been identified. RLS susceptibility also has been related to iron. We therefore asked whether known iron-related genes are candidates for association with RLS and, vice versa, whether known RLS-associated loci influence iron parameters in serum. RLS/control samples (n=954/1814 in the discovery step, 735/736 in replication 1, and 736/735 in replication 2) were tested for association with SNPs located within 4 Mb intervals surrounding each gene from a list of 111 iron-related genes using a discovery threshold of P=5 × 10−4. Two population cohorts (KORA F3 and F4 with together n=3447) were tested for association of six known RLS loci with iron, ferritin, transferrin, transferrin-saturation, and soluble transferrin receptor. Results were negative. None of the candidate SNPs at the iron-related gene loci was confirmed significantly. An intronic SNP, rs2576036, of KATNAL2 at 18q21.1 was significant in the first (P=0.00085) but not in the second replication step (joint nominal P-value=0.044). Especially, rs1800652 (C282Y) in the HFE gene did not associate with RLS. Moreover, SNPs at the known RLS loci did not significantly affect serum iron parameters in the KORA cohorts. In conclusion, the correlation between RLS and iron parameters in serum may be weaker than assumed. Moreover, in a general power analysis, we show that genetic effects are diluted if they are transmitted via an intermediate trait to an end-phenotype. Sample size formulas are provided for small effect sizes.
doi:10.1038/ejhg.2012.193
PMCID: PMC3598324  PMID: 22929029
restless legs syndrome; iron parameters; MEIS1 haplotype; power calculation; linear regression; logistic regression
2.  Niemann-Pick C Disease Gene Mutations and Age-Related Neurodegenerative Disorders 
PLoS ONE  2013;8(12):e82879.
Niemann-Pick type C (NPC) disease is a rare autosomal-recessively inherited lysosomal storage disorder caused by mutations in NPC1 (95%) or NPC2. Given the highly variable phenotype, diagnosis is challenging and particularly late-onset forms with predominantly neuropsychiatric presentations are likely underdiagnosed. Pathophysiologically, genetic alterations compromising the endosomal/lysosomal system are linked with age-related neurodegenerative disorders. We sought to examine a possible association of rare sequence variants in NPC1 and NPC2 with Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD) and progressive supranuclear palsy (PSP), and to genetically determine the proportion of potentially misdiagnosed NPC patients in these neurodegenerative conditions. By means of high-resolution melting, we screened the coding regions of NPC1 and NPC2 for rare genetic variation in a homogenous German sample of patients clinically diagnosed with PD (n = 563), FTLD (n = 133) and PSP (n = 94), and 846 population-based controls. The frequencies of rare sequence variants in NPC1/2 did not differ significantly between patients and controls. Disease-associated NPC1/2 mutations were found in six PD patients (1.1%) and seven control subjects (0.8%), but not in FTLD or PSP. All rare variation was detected in the heterozygous state and no compound heterozygotes were observed. Our data do not support the hypothesis that rare NPC1/2 variants confer susceptibility for PD, FTLD, or PSP in the German population. Misdiagnosed NPC patients were not present in our samples. However, further assessment of NPC disease genes in age-related neurodegeneration is warranted.
doi:10.1371/journal.pone.0082879
PMCID: PMC3875432  PMID: 24386122
3.  Rare variants in LRRK1 and Parkinson's disease 
Neurogenetics  2013;15:49-57.
Approximately 20 % of individuals with Parkinson's disease (PD) report a positive family history. Yet, a large portion of causal and disease-modifying variants is still unknown. We used exome sequencing in two affected individuals from a family with late-onset PD to identify 15 potentially causal variants. Segregation analysis and frequency assessment in 862 PD cases and 1,014 ethnically matched controls highlighted variants in EEF1D and LRRK1 as the best candidates. Mutation screening of the coding regions of these genes in 862 cases and 1,014 controls revealed several novel non-synonymous variants in both genes in cases and controls. An in silico multi-model bioinformatics analysis was used to prioritize identified variants in LRRK1 for functional follow-up. However, protein expression, subcellular localization, and cell viability were not affected by the identified variants. Although it has yet to be proven conclusively that variants in LRRK1 are indeed causative of PD, our data strengthen a possible role for LRRK1 in addition to LRRK2 in the genetic underpinnings of PD but, at the same time, highlight the difficulties encountered in the study of rare variants identified by next-generation sequencing in diseases with autosomal dominant or complex patterns of inheritance.
Electronic supplementary material
The online version of this article (doi:10.1007/s10048-013-0383-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s10048-013-0383-8
PMCID: PMC3968516  PMID: 24241507
Parkinson's disease; LRRK1; EEF1D; Exome sequencing
4.  Rare Variants in PLXNA4 and Parkinson’s Disease 
PLoS ONE  2013;8(11):e79145.
Approximately 20% of individuals with Parkinson’s disease (PD) report a positive family history. Yet, a large portion of causal and disease-modifying variants is still unknown. We used exome sequencing in two affected individuals from a family with late-onset familial PD followed by frequency assessment in 975 PD cases and 1014 ethnically-matched controls and linkage analysis to identify potentially causal variants. Based on the predicted penetrance and the frequencies, a variant in PLXNA4 proved to be the best candidate and PLXNA4 was screened for additional variants in 862 PD cases and 940 controls, revealing an excess of rare non-synonymous coding variants in PLXNA4 in individuals with PD. Although we cannot conclude that the variant in PLXNA4 is indeed the causative variant, these findings are interesting in the light of a surfacing role of axonal guidance mechanisms in neurodegenerative disorders but, at the same time, highlight the difficulties encountered in the study of rare variants identified by next-generation sequencing in diseases with autosomal dominant or complex patterns of inheritance.
doi:10.1371/journal.pone.0079145
PMCID: PMC3823607  PMID: 24244438
5.  Impairment of brainstem implicit learning paradigms differentiates multiple system atrophy (MSA) from idiopathic Parkinson syndrome 
BMJ Open  2013;3(9):e003098.
Objectives
Learning as measured by eyeblink classical conditioning is preserved in patients with idiopathic Parkinson's disease, but severely affected in patients with progressive supranuclear palsy. We here sought to clarify whether procedural learning is impaired in multiple system atrophy (MSA), and whether it may be helpful for the differentiation of parkinsonian syndromes.
Design
We investigated learning using (1) eyeblink classical conditioning with a delay (interstimulus interval 0 ms) and a trace (600 ms) paradigm and (2) a serial reaction time task.
Setting
Participants were recruited from academic research centres.
Participants
11 patients with MSA and 11 healthy controls.
Results
Implicit learning in eyeblink classical conditioning (acquisition of conditioned responses) as well as the serial reaction time task measures of implicit learning (reaction time change) are impaired in patients with MSA as compared with controls, whereas explicit learning as measured by the sequence recall of the serial reaction time task is relatively preserved.
Analysis
We hypothesise that the learning deficits of patients with MSA are due to lesions of cerebellar and connected brainstem areas.
Conclusions
A retrospective synopsis of these novel data on patients with MSA and groups of patients with idiopathic Parkinson's disease and progressive supranuclear palsy studied earlier suggest that eyeblink classical conditioning may contribute to the early differentiation of atypical Parkinson syndromes from idiopathic Parkinson's disease. This hypothesis should be tested in a prospective trial.
doi:10.1136/bmjopen-2013-003098
PMCID: PMC3773641  PMID: 24038003
Parkinsons disease; Learning
6.  No Difference in Sleep and RBD between Different Types of Patients with Multiple System Atrophy: A Pilot Video-Polysomnographical Study 
Sleep Disorders  2013;2013:258390.
Background. Patients with multiple system atrophy (MSA), similarly to patients with alpha-synucleinopathies, can present with different sleep problems. We sought to analyze sleep problems in the two subtypes of the disease MSA cerebellar type (MSA-C) and MSA parkinsonian type (MSA-P), paying special attention to REM sleep disturbances and periodic limb movements (PLMs). Methods. In the study we included 11 MSA-C and 27 MSA-P patients who underwent one night polysomnography. For the analysis, there were 37 valid polysomnographic studies. Results. Sleep efficiency was decreased in both groups (MSA-C, 64.27% ± 12.04%; MSA-P, 60.64% ± 6.01%). The PLM indices using standard measures, in sleep (PLMS) and while awake (PLMW), were high in both groups (MSA-C patients: PLMS index 72 ± 65, PLMW index 38 ± 33; MSA-P patients: PLMS index 66 ± 63, PLMW index 48 ± 37). Almost one-third of the MSA patients of both groups presented features of RLS on video-polysomnography. RBD was described in 8/11 (73%) patients with MSA-C and 19/25 (76%) patients with MSA-P (P = 0.849). Conclusion. Our results showed very similar polysomnographic results for both MSA-P and MSA-C patients as a probable indicator for the similar pathologic mechanism of the disease and especially of its sleep problems.
doi:10.1155/2013/258390
PMCID: PMC3654360  PMID: 23766915
7.  α-Synuclein in human cerebrospinal fluid is principally derived from neurons of the central nervous system 
Journal of Neural Transmission  2012;119(7):739-746.
The source of Parkinson disease-linked α-synuclein (aSyn) in human cerebrospinal fluid (CSF) remains unknown. We decided to measure the concentration of aSyn and its gradient in human CSF specimens and compared it with serum to explore its origin. We correlated aSyn concentrations in CSF versus serum (QaSyn) to the albumin quotient (Qalbumin) to evaluate its relation to blood–CSF barrier function. We also compared aSyn with several other CSF constituents of either central or peripheral sources (or both) including albumin, neuron-specific enolase, β-trace protein and total protein content. Finally, we examined whether aSyn is present within the structures of the choroid plexus (CP). We observed that QaSyn did not rise or fall with Qalbumin values, a relative measure of blood–CSF barrier integrity. In our CSF gradient analyses, aSyn levels decreased slightly from rostral to caudal fractions, in parallel to the recorded changes for neuron-specific enolase; the opposite trend was recorded for total protein, albumin and β-trace protein. The latter showed higher concentrations in caudal CSF fractions due to the diffusion-mediated transfer of proteins from blood and leptomeninges into CSF in the lower regions of the spine. In postmortem sections of human brain, we detected highly variable aSyn reactivity within the epithelial cell layer of CP in patients diagnosed with a range of neurological diseases; however, in sections of mice that express only human SNCA alleles (and in those without any Snca gene expression), we detected no aSyn signal in the epithelial cells of the CP. We conclude from these complementary results that despite its higher levels in peripheral blood products, neurons of the brain and spinal cord represent the principal source of aSyn in human CSF.
doi:10.1007/s00702-012-0784-0
PMCID: PMC3378837  PMID: 22426833
α-Synuclein; Cerebrospinal fluid; Blood–CSF barrier; Biomarker; Choroid plexus
8.  Novel SCARB2 mutation in action myoclonus-renal failure syndrome and evaluation of SCARB2 mutations in isolated AMRF features 
BMC Neurology  2011;11:134.
Background
Action myoclonus-renal failure syndrome is a hereditary form of progressive myoclonus epilepsy associated with renal failure. It is considered to be an autosomal-recessive disease related to loss-of-function mutations in SCARB2. We studied a German AMRF family, additionally showing signs of demyelinating polyneuropathy and dilated cardiomyopathy.
To test the hypothesis whether isolated appearance of individual AMRF syndrome features could be related to heterozygote SCARB2 mutations, we screened for SCARB2 mutations in unrelated patients showing isolated AMRF features.
Methods
In the AMRF family all exons of SCARB2 were analyzed by Sanger sequencing. The mutation screening of unrelated patients with isolated AMRF features affected by either epilepsy (n = 103, progressive myoclonus epilepsy or generalized epilepsy), demyelinating polyneuropathy (n = 103), renal failure (n = 192) or dilated cardiomyopathy (n = 85) was performed as high resolution melting curve analysis of the SCARB2 exons.
Results
A novel homozygous 1 bp deletion (c.111delC) in SCARB2 was found by sequencing three affected homozygous siblings of the affected family. A heterozygous sister showed generalized seizures and reduction of nerve conduction velocity in her legs. No mutations were found in the epilepsy, renal failure or dilated cardiomyopathy samples. In the polyneuropathy sample two individuals with demyelinating disease were found to be carriers of a SCARB2 frameshift mutation (c.666delCCTTA).
Conclusions
Our findings indicate that demyelinating polyneuropathy and dilated cardiomyopathy are part of the action myoclonus-renal failure syndrome. Moreover, they raise the possibility that in rare cases heterozygous SCARB2 mutations may be associated with PNP features.
doi:10.1186/1471-2377-11-134
PMCID: PMC3222607  PMID: 22032306
9.  Frequency of impulse control behaviours associated with dopaminergic therapy in restless legs syndrome 
BMC Neurology  2011;11:117.
Background
Low doses of dopamine agonists (DA) and levodopa are effective in the treatment of restless legs syndrome (RLS). A range of impulse control and compulsive behaviours (ICBs) have been reported following the use of DAs and levodopa in patients with Parkinson's disease. With this study we sought to assess the cross-sectional prevalence of impulse control behaviours (ICBs) in restless legs syndrome (RLS) and to determine factors associated with ICBs in a population cohort in Germany.
Methods
Several questionnaires based on validated and previously used instruments for assessment of ICBs were mailed out to patients being treated for RLS. Final diagnoses of ICBs were based on stringent diagnostic criteria after psychiatric interviews were performed.
Results
10/140 RLS patients of a clinical cohort (7.1%) were finally diagnosed with ICBs, 8 of 10 on dopamine agonist (DA) therapy, 2 of 10 on levodopa. 8 of the 10 affected patients showed more than one type of abnormal behaviour. Among those who responded to the questionnaires 6/140 [4.3%] revealed binge eating, 5/140 [3.6%] compulsive shopping, 3/140 [2.1%] pathological gambling, 3/140 [2.1%] punding, and 2/140 [1.4%] hypersexuality in psychiatric assessments. Among those who did not respond to questionnaires, 32 were randomly selected and interviewed: only 1 patient showed positive criteria of ICBs with compulsive shopping and binge eating. ICBs were associated with higher DA dose (p = 0.001), younger RLS onset (p = 0.04), history of experimental drug use (p = 0.002), female gender (p = 0.04) and a family history of gambling disorders (p = 0.02), which accounted for 52% of the risk variance.
Conclusion
RLS patients treated with dopaminergic agents and dopamine agonists in particular, should be forewarned of potential side effects. A careful history of risk factors should be taken.
doi:10.1186/1471-2377-11-117
PMCID: PMC3195705  PMID: 21955669
Restless legs syndrome; impulse control disorders; dopamine agonist; gambling; levodopa
10.  Correction: Genome-Wide Association Study Identifies Novel Restless Legs Syndrome Susceptibility Loci on 2p14 and 16q12.1 
PLoS Genetics  2011;7(8):10.1371/annotation/393ad2d3-df4f-4770-87bc-00bfabf79362.
doi:10.1371/annotation/393ad2d3-df4f-4770-87bc-00bfabf79362
PMCID: PMC3154083
11.  Genome-Wide Association Study Identifies Novel Restless Legs Syndrome Susceptibility Loci on 2p14 and 16q12.1 
PLoS Genetics  2011;7(7):e1002171.
Restless legs syndrome (RLS) is a sensorimotor disorder with an age-dependent prevalence of up to 10% in the general population above 65 years of age. Affected individuals suffer from uncomfortable sensations and an urge to move in the lower limbs that occurs mainly in resting situations during the evening or at night. Moving the legs or walking leads to an improvement of symptoms. Concomitantly, patients report sleep disturbances with consequences such as reduced daytime functioning. We conducted a genome-wide association study (GWA) for RLS in 922 cases and 1,526 controls (using 301,406 SNPs) followed by a replication of 76 candidate SNPs in 3,935 cases and 5,754 controls, all of European ancestry. Herein, we identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972, P = 9.03 × 10−11, OR = 1.23) and a locus on 16q12.1 (rs3104767, P = 9.4 × 10−19, OR = 1.35) in a linkage disequilibrium block of 140 kb containing the 5′-end of TOX3 and the adjacent non-coding RNA BC034767.
Author Summary
Restless legs syndrome (RLS) is one of the most common neurological disorders. Patients with RLS suffer from an urge to move the legs and unpleasant sensations located mostly deep in the calf. Symptoms mainly occur in resting situations in the evening or at night. As a consequence, initiation and maintenance of sleep become defective. Here, we performed a genome-wide association study to identify common genetic variants increasing the risk for disease. The genome-wide phase included 922 cases and 1,526 controls, and candidate SNPs were replicated in 3,935 cases and 5,754 controls, all of European ancestry. We identified two new RLS–associated loci: an intergenic region on chromosome 2p14 and a locus on 16q12.1 in a linkage disequilibrium block containing the 5′-end of TOX3 and the adjacent non-coding RNA BC034767. TOX3 has been implicated in the development of breast cancer. The physiologic role of TOX3 and BC034767 in the central nervous system and a possible involvement of these two genes in RLS pathogenesis remain to be established.
doi:10.1371/journal.pgen.1002171
PMCID: PMC3136436  PMID: 21779176
12.  Algorithms for the diagnosis and treatment of restless legs syndrome in primary care 
BMC Neurology  2011;11:28.
Background
Restless legs syndrome (RLS) is a neurological disorder with a lifetime prevalence of 3-10%. in European studies. However, the diagnosis of RLS in primary care remains low and mistreatment is common.
Methods
The current article reports on the considerations of RLS diagnosis and management that were made during a European Restless Legs Syndrome Study Group (EURLSSG)-sponsored task force consisting of experts and primary care practioners. The task force sought to develop a better understanding of barriers to diagnosis in primary care practice and overcome these barriers with diagnostic and treatment algorithms.
Results
The barriers to diagnosis identified by the task force include the presentation of symptoms, the language used to describe them, the actual term "restless legs syndrome" and difficulties in the differential diagnosis of RLS.
Conclusion
The EURLSSG task force reached a consensus and agreed on the diagnostic and treatment algorithms published here.
doi:10.1186/1471-2377-11-28
PMCID: PMC3056753  PMID: 21352569
13.  Treatment of moderate to severe restless legs syndrome: 2-year safety and efficacy of rotigotine transdermal patch 
BMC Neurology  2010;10:86.
Background
Rotigotine is a unique dopamine agonist with activity across D1 through D5 receptors as well as select adrenergic and serotonergic sites. This study reports the 2-year follow-up safety and efficacy data of an ongoing open-label multicenter extension study (NCT00498186) of transdermal rotigotine in patients with moderate to severe restless legs syndrome (RLS).
Methods
Patients received a once-daily patch application of an individually optimized dose of rotigotine between 0.5 mg/24 h to 4 mg/24 h. Safety assessments included adverse events (AEs) and efficacy was measured by the International RLS Study Group Severity Rating Scale (IRLS), RLS-6 scales and Clinical Global Impression (CGI). Quality of life (QoL) was measured by QoL-RLS.
Results
Of 310 patients who completed a 6-week placebo-controlled trial (SP709), 295 (mean age 58 ± 10 years, 66% females) were included in the open-label trial SP710. 64.7% (190/295 patients) completed the 2-year follow-up; 29 patients discontinued during the second year. Mean daily rotigotine dose after 2 years was 2.93 ± 1.14 mg/24 h with a 2.9% dose increase from year 1. Rotigotine was generally well tolerated. The rate of typical dopaminergic side effects, nausea and fatigue, was low (0.9% and 2.3%, respectively) during the second year; application site reactions were frequent but lower than in year 1 (16.4% vs. 34.5%). The IRLS total score improved from baseline of SP709 (27.8 ± 5.9) by 17.2 ± 9.2 in year 2 completers. Similar improvements were observed in RLS-6 scales, CGI scores and QoL-RLS. The responder rate in the CGI change item 2 ("much" and "very much" improved) was 95% after year 2.
Conclusions
Transdermal rotigotine is an efficacious and well-tolerated long-term treatment option for patients with moderate to severe RLS with a high retention rate during 2 years of therapy.
Trial registration
NCT00498186
doi:10.1186/1471-2377-10-86
PMCID: PMC2958158  PMID: 20920156
14.  Combined Analysis of CSF Tau, Aβ42, Aβ1–42% and Aβ1–40ox% in Alzheimer's Disease, Dementia with Lewy Bodies and Parkinson's Disease Dementia 
We studied the diagnostic value of CSF Aβ42/tau versus low Aβ1–42% and high Aβ1–40ox% levels for differential diagnosis of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), respectively. CSF of 45 patients with AD, 15 with DLB, 21 with Parkinson's disease dementia (PDD), and 40 nondemented disease controls (NDC) was analyzed by Aβ-SDS-PAGE/immunoblot and ELISAs (Aβ42 and tau). Aβ42/tau lacked specificity in discriminating AD from DLB and PDD. Best discriminating biomarkers were Aβ1–42% and Aβ1–40ox% for AD and DLB, respectively. AD and DLB could be differentiated by both Aβ1–42% and Aβ1–40ox% with an accuracy of 80% at minimum. Thus, we consider Aβ1–42% and Aβ1–40ox% to be useful biomarkers for AD and DLB, respectively. We propose further studies on the integration of Aβ1–42% and Aβ1–40ox% into conventional assay formats. Moreover, future studies should investigate the combination of Aβ1–40ox% and CSF alpha-synuclein for the diagnosis of DLB.
doi:10.4061/2010/761571
PMCID: PMC2938459  PMID: 20862375
15.  Progressive development of augmentation during long-term treatment with levodopa in restless legs syndrome: results of a prospective multi-center study 
Journal of Neurology  2009;257(2):230-237.
The European Restless Legs Syndrome (RLS) Study Group performed the first multi-center, long-term study systematically evaluating RLS augmentation under levodopa treatment. This prospective, open-label 6-month study was conducted in six European countries and included 65 patients (85% treatment naive) with idiopathic RLS. Levodopa was flexibly up-titrated to a maximum dose of 600 mg/day. Presence of augmentation was diagnosed independently by two international experts using established criteria. In addition to the augmentation severity rating scale (ASRS), changes in RLS severity (International RLS severity rating scale (IRLS), clinical global impression (CGI)) were analyzed. Sixty patients provided evaluable data, 35 completed the trial and 25 dropped out. Augmentation occurred in 60% (36/60) of patients, causing 11.7% (7/60) to drop out. Median time to occurrence of augmentation was 71 days. The mean maximum dose of levodopa was 311 mg/day (SD: 105). Patients with augmentation compared to those without were significantly more likely to be on higher doses of levodopa (≥300 mg, 83 vs. 54%, P = 0.03) and to show less improvement of symptom severity (IRLS, P = 0.039). Augmentation was common with levodopa, but could be tolerated by most patients during this 6-month trial. Patients should be followed over longer periods to determine if dropout rates increase with time.
doi:10.1007/s00415-009-5299-8
PMCID: PMC3085743  PMID: 19756826
Restless legs syndrome (RLS); Augmentation; Diagnosis; Rating scale; Clinical study
16.  Parkinson’s disease sleep scale, sleep logs, and actigraphy in the evaluation of sleep in parkinsonian patients 
Journal of Neurology  2009;256(9):1480-1484.
The aim of this study was to compare the results of the day-to-day self-evaluation of sleep quality by sleep logs with Parkinson’s disease sleep scale (PDSS) in Parkinson’s disease (PD) patients. Actigraphy was used as an independent analysis of nighttime activity interfering with sleep. A total of 71 idiopathic PD patients and 21 age- and sex-matched normal individuals lacking any type of sleep disturbance were recruited. Sleep was evaluated by PDSS, 7-d sleep log and actigraphy. Sleep logs and PDSS showed reduced sleep quality and daytime somnolence scores in moderate/severe PD patients as compared to healthy controls. Significant correlations were found between sleep quality in sleep logs and all domains of PDSS sleep quality, except for the presence of nocturia, which correlated with nocturnal activity. PD severity and depression were the only predictors of reduced sleep quality. The retrospective and day-to-day sleep self-evaluations were coincident. Reduced sleep quality was related to increased PD severity and depression scores.
doi:10.1007/s00415-009-5141-3
PMCID: PMC3085768  PMID: 19404716
Sleep logs; Parkinson’s disease; Actigraphy; Sleep disorders; Sleep evaluation
17.  The Tumorigenicity of Mouse Embryonic Stem Cells and In Vitro Differentiated Neuronal Cells Is Controlled by the Recipients' Immune Response 
PLoS ONE  2008;3(7):e2622.
Embryonic stem (ES) cells have the potential to differentiate into all cell types and are considered as a valuable source of cells for transplantation therapies. A critical issue, however, is the risk of teratoma formation after transplantation. The effect of the immune response on the tumorigenicity of transplanted cells is poorly understood. We have systematically compared the tumorigenicity of mouse ES cells and in vitro differentiated neuronal cells in various recipients. Subcutaneous injection of 1×106 ES or differentiated cells into syngeneic or allogeneic immunodeficient mice resulted in teratomas in about 95% of the recipients. Both cell types did not give rise to tumors in immunocompetent allogeneic mice or xenogeneic rats. However, in 61% of cyclosporine A-treated rats teratomas developed after injection of differentiated cells. Undifferentiated ES cells did not give rise to tumors in these rats. ES cells turned out to be highly susceptible to killing by rat natural killer (NK) cells due to the expression of ligands of the activating NK receptor NKG2D on ES cells. These ligands were down-regulated on differentiated cells. The activity of NK cells which is not suppressed by cyclosporine A might contribute to the prevention of teratomas after injection of ES cells but not after inoculation of differentiated cells. These findings clearly point to the importance of the immune response in this process. Interestingly, the differentiated cells must contain a tumorigenic cell population that is not present among ES cells and which might be resistant to NK cell-mediated killing.
doi:10.1371/journal.pone.0002622
PMCID: PMC2440803  PMID: 18612432
18.  Monthly intravenous methylprednisolone in relapsing-remitting multiple sclerosis - reduction of enhancing lesions, T2 lesion volume and plasma prolactin concentrations 
BMC Neurology  2006;6:19.
Background
Intravenous methylprednisolone (IV-MP) is an established treatment for multiple sclerosis (MS) relapses, accompanied by rapid, though transient reduction of gadolinium enhancing (Gd+) lesions on brain MRI. Intermittent IV-MP, alone or with immunomodulators, has been suggested but insufficiently studied as a strategy to prevent relapses.
Methods
In an open, single-cross-over study, nine patients with relapsing-remitting MS (RR-MS) underwent cranial Gd-MRI once monthly for twelve months. From month six on, they received a single i.v.-infusion of 500 mg methylprednisolone (and oral tapering for three days) after the MRI. Primary outcome measure was the mean number of Gd+ lesions during treatment vs. baseline periods; T2 lesion volume and monthly plasma concentrations of cortisol, ACTH and prolactin were secondary outcome measures. Safety was assessed clinically, by routine laboratory and bone mineral density measurements. Soluble immune parameters (sTNF-RI, sTNF-RII, IL1-ra and sVCAM-1) and neuroendocrine tests (ACTH test, combined dexamethasone/CRH test) were additionally analyzed.
Results
Comparing treatment to baseline periods, the number of Gd+ lesions/scan was reduced in eight of the nine patients, by a median of 43.8% (p = 0.013, Wilcoxon). In comparison, a pooled dataset of 83 untreated RR-MS patients from several studies, selected by the same clinical and MRI criteria, showed a non-significant decrease by a median of 14% (p = 0.32). T2 lesion volume decreased by 21% during treatment (p = 0.001). Monthly plasma prolactin showed a parallel decline (p = 0.027), with significant cross-correlation with the number of Gd+ lesions. Other hormones and immune system variables were unchanged, as were ACTH test and dexamethasone-CRH test. Treatment was well tolerated; routine laboratory and bone mineral density were unchanged.
Conclusion
Monthly IV-MP reduces inflammatory activity and T2 lesion volume in RR-MS.
doi:10.1186/1471-2377-6-19
PMCID: PMC1501038  PMID: 16719908
19.  Rotigotine Effects on Early Morning Motor Function and Sleep in Parkinson's Disease: A Double-Blind, Randomized, pLacebo-Controlled Study (RECOVER) 
Movement Disorders  2010;26(1):90-99.
In a multinational, double-blind, placebo-controlled trial (NCT00474058), 287 subjects with Parkinson's disease (PD) and unsatisfactory early-morning motor symptom control were randomized 2:1 to receive rotigotine (2–16 mg/24 hr [n = 190]) or placebo (n = 97). Treatment was titrated to optimal dose over 1–8 weeks with subsequent dose maintenance for 4 weeks. Early-morning motor function and nocturnal sleep disturbance were assessed as coprimary efficacy endpoints using the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (Motor Examination) measured in the early morning prior to any medication intake and the modified Parkinson's Disease Sleep Scale (PDSS-2) (mean change from baseline to end of maintenance [EOM], last observation carried forward). At EOM, mean UPDRS Part III score had decreased by −7.0 points with rotigotine (from a baseline of 29.6 [standard deviation (SD) 12.3] and by −3.9 points with placebo (baseline 32.0 [13.3]). Mean PDSS-2 total score had decreased by −5.9 points with rotigotine (from a baseline of 19.3 [SD 9.3]) and by −1.9 points with placebo (baseline 20.5 [10.4]). This represented a significantly greater improvement with rotigotine compared with placebo on both the UPDRS Part III (treatment difference: −3.55 [95% confidence interval (CI) −5.37, −1.73]; P = 0.0002) and PDSS-2 (treatment difference: −4.26 [95% CI −6.08, −2.45]; P < 0.0001). The most frequently reported adverse events were nausea (placebo, 9%; rotigotine, 21%), application site reactions (placebo, 4%; rotigotine, 15%), and dizziness (placebo, 6%; rotigotine 10%). Twenty-four-hour transdermal delivery of rotigotine to PD patients with early-morning motor dysfunction resulted in significant benefits in control of both motor function and nocturnal sleep disturbances. © 2010 Movement Disorder Society
doi:10.1002/mds.23441
PMCID: PMC3072524  PMID: 21322021
dopamine agonist; rotigotine; transdermal; motor function; sleep; quality of life

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