Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine disorder caused by a CAG repeat expansion... more Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine disorder caused by a CAG repeat expansion in the coding region of a gene encoding ataxin-3. To study putative alterations of gene expression induced by expanded ataxin-3, we performed PCRbased cDNA subtractive hybridization in a cell culture model of SCA3. In rat mesencephalic CSM14.1 cells stably expressing expanded ataxin-3, we found a significant upregulation of mRNAs encoding the endopeptidase matrix metalloproteinase 2 (MMP-2), the transmembrane protein amyloid precursor protein, the interleukin-1 receptor-related Fos-inducible transcript, and the cytokine stromal cell-derived factor 1␣ (SDF1␣). Immunohistochemical studies of the corresponding or associated proteins in human SCA3 brain tissue confirmed these findings, showing increased expression of MMP-2 and amyloid -protein (A) in pontine neurons containing nuclear inclusions. In addition, extracellular A-immunoreactive deposits were detected in human SCA3 pons. Furthermore, pontine neurons of SCA3 brains strongly expressed the antiinflammatory interleukin-1 receptor antagonist, the proinflammatory cytokine interleukin-1, and the proinflammatory chemokine SDF1. Finally, increased numbers of reactive astrocytes and activated microglial cells were found in SCA3 pons. These results suggest that inflammatory processes are involved in the pathogenesis of SCA3.
The proto-oncogene Bcl-2 rescues cells from a wide variety of insults. Recent evidence suggests t... more The proto-oncogene Bcl-2 rescues cells from a wide variety of insults. Recent evidence suggests that Bcl-2 protects against free radicals and that it increases mitochondrial calcium-buffering capacity. The neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyride (MPTP) is thought to involve both mitochondrial dysfunction and free radical generation. We therefore investigated MPTP neurotoxicity in both Bcl-2 overexpressing mice and littermate controls. MPTP-induced depletion of dopamine and loss of [3H]mazindol binding were significantly attenuated in Bcl-2 overexpressing mice. Protection was more profound with an acute dosing regimen than with daily MPTP administration over 5 d. 1-Methyl-4-phenylpyridinium (MPP+) levels after MPTP administration were similar in Bcl-2 overexpressing mice and littermates. Bcl-2 blocked MPP+-induced activation of caspases. MPTP-induced increases in free 3-nitrotyrosine levels were blocked in Bcl-2 overexpressing mice. These results indicate that Bcl...
Prior to patent expiry of a drug, the manufacturer will generally increase marketing efforts in o... more Prior to patent expiry of a drug, the manufacturer will generally increase marketing efforts in order to maintain market-share. The introduction of generics will lead to strong competition, forcing the original patent holder to change their marketing strategy. These effects, together with other factors (e.g. governmental price legislation) may lead to increasing drug expenditures. In order to increase price competition the Dutch government plans to modernize the drug reimbursement system, which is conceived to inadequately control drug prices. In particular, drug prices may not relevantly decrease due to lack of incentives for price competition. OBJECTIVES: To investigate the magnitude of effects on market-share and drug prices, we evaluated trends in drug volume and costs after patent expiry for enalapril, fluoxetine and ranitidine in the The Netherlands. METHODS: Governmental price, volume and reimbursement policies were evaluated in order to provide a framework for developments after patent expiry. Drug use was measured as Defined Daily Doses (DDD) per 1000 population, derived from the InterAction DataBase, comprising pharmacies in the North of the The Netherlands. Drug costs were calculated per DDD. Estimated trendlines for drug costs and share of drugs in the different trade-channels (specialité, parallel, generic) were compared. RESULTS: After the patent expired, costs per DDD-for enalapril, fluoxetine and ranitidine-decreased with 61%, 51% and 69% respectively. For enalapril and fluoxetine statistical significant differences in trendlines were found. For all investigated drugs, generic products rapidly took over the majority of the market-share (over 75%). Nearly all new users received a generic drug after patent expiry. Further results will be presented on omeprazol and simvastatine, with very recent patent expiries. CONCLUSIONS: Our findings indicate that patent expiry may cause price competition leading to cost decreases. This is opposite the current opinion that the drug reimbursement system would inadequately control drug prices.
Glutathione levels are decreased in the substantia nigra of patients with Parkinson&#... more Glutathione levels are decreased in the substantia nigra of patients with Parkinson's disease. We studied whether glutathione depletion contributes to dopaminergic cell death using a specific inhibitor of glutathione biosynthesis, L-buthionine sulfoximine (BSO). We found no significant reduction of tyrosine hydroxylase-positive cells in the substantia nigra pars compacta (SNpc) when BSO was administered systemically to preweanling mice or locally to the SNpc of adult rats. However, the combination of BSO with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in preweanling mice and the combination of nigral injections of BSO with intrastriatal injections of MPP+ (1-methyl-4-phenylpyridinium), the active metabolite of MPTP in adult rats, potentiated the toxic effects of MPTP and MPP+ on nigral neurones. Our data show that glutathione depletion can result in cell death if the nigrostriatal system is metabolically compromised.
identifi ed (the Index Date was defi ned as the earliest ACE). Patients age ≥18, ≥6 months eligib... more identifi ed (the Index Date was defi ned as the earliest ACE). Patients age ≥18, ≥6 months eligibility pre-and post-Index Date, ≥1 statin fi ll and no statin augmenting fi ll 6 months before the Index Date, and ≥1 FF or SM fi ll 6 months after the Index Date (Cohort ID Period) were included. Patients with fi lls for alternative statin augmenting therapies or SCE during the Cohort ID Period were excluded. The primary outcome was SCE. Secondary outcomes were cerebrovascular event risk and eventrelated medical costs. Event risk was compared using Cox proportional hazards models, while costs were compared via generalized linear models. Multivariate analyses controlled for age, gender, geography, co-morbidities, concomitant medications, statin potency, and severity of initial ACE. RESULTS: A total of 24,625 patients added FF (n = 399) or maintained SM (n = 24,226) 6-months after initial ACE while meeting study inclusion/exclusion criteria. FF patients were younger (59 ± 10 vs. 65 ± 12, P < 0.0001), less likely female (27% vs. 34%, P = 0.002), and had shorter follow-up (358 vs. 443 days, P < 0.0001). FF patients had lower frequency of SCE (20%) vs. SM (25%), with an unadjusted hazard ratio (HR) of 0.88 (95%CI: 0.71-1.10). a similar directional trend was observed for cerebrovascular events (HR: 0.74; 95% CI: 0.40-1.37). Multivariate analyses of SCE risk demonstrated consistent directional benefi t (HR: 0.93; 95% CI: 0.74-1.16). Clinical fi ndings corresponded with 25% lower adjusted annual event-related costs compared to SM (0.75; 95% CI: 0.57-0.97; p = 0.0306). CONCLUSIONS: The positive clinical benefi ts from this real-world analysis provide evidence supporting ability of FF to reduce both SCE risk and event-related medical costs following ACE.
A common subset of genetic risk factors for Parkinson&#39;s disease (PD) and essential tremor... more A common subset of genetic risk factors for Parkinson&#39;s disease (PD) and essential tremor (ET) has been postulated. Recently, an association between the dopamine D(3) receptor (DRD3) Ser9Gly polymorphism and ET has been reported. We studied whether PD tremor is influenced by Ser9Gly in a genetic association study based on the gene bank of the German Competence Network on Parkinson&#39;s disease. The study included analyses of motor predominance (mixed, hypokinetic, and tremor), and tremor type (resting, postural, and action). We did not identify any effect of DRD3 Ser9Gly on tremor in PD, even when regarding various symptom combinations to avoid missing a weak effect on the phenotype. Additional studies incorporating symptoms at disease onset, and grading of tremor response to dopaminergic therapy, are warranted.
Nitrous oxide has multiple deleterious effects on cobalamin metabolism and causes decreases in ac... more Nitrous oxide has multiple deleterious effects on cobalamin metabolism and causes decreases in activities of both mammalian cobalamin dependent enzymes in rats. J Clin Invest 1981;67:1270-1283. 24. Carmel R, Karnaze DS, Weiner JM. Neurologic abnormalities in cobalamin deficiency are associated with higher cobalamin "analogue" values than are haematological abnormalities.
Figure. 18 F-fluorodeoxyglucose (FDG) PET during a relapse after withdrawal of methotrexate. FDG ... more Figure. 18 F-fluorodeoxyglucose (FDG) PET during a relapse after withdrawal of methotrexate. FDG uptake is enhanced in the right caput nuclei caudati (CNC) as compared with the contralateral side. Regions of interest in this plane revealed maximal standard uptake values of 6.3 (right CNC) and 5.8 (left CNC).
Objective: Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), known as atypi... more Objective: Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), known as atypical parkinsonian syndromes (APS), are neurodegenerative disorders with severe disability and decreased life expectancy. Little is known about the health-related quality of life (HrQoL) and its determinants in patients with those disorders. The objective of our cross-sectional study was to evaluate the HrQoL in patients with APS and to identify the determinants of HrQoL. Methods: A total of 101 consecutive patients with MSA (n = 54) and PSP (n = 47) were recruited in four German neurological centers. Disease severity was assessed using the Hoehn and Yahr stages and the Unified MSA Rating Scale. The HrQoL was evaluated using the EuroQol instrument (EQ-5D and EQ-VAS). Independent determinants of HrQoL were identified in multiple regression analyses. Results: The mean EQ-VAS score was 52% lower than that reported for the general population (36.9 ± 18.3 vs. 77.4 ± 19.0). Of the study particip...
The disease-specific Unified Multiple System Atrophy Rating Scale (UMSARS) has been developed rec... more The disease-specific Unified Multiple System Atrophy Rating Scale (UMSARS) has been developed recently and validated for assessing disease severity in multiple system atrophy (MSA). Here, we aimed at (1) assessing rates of disease progression in MSA and (2) validating UMSARS for sensitivity to change over time. Impairment was assessed at two time points 12 months apart using UMSARS Part I (historical review), UMSARS Part II (motor examination), as well as measures of global disease severity, including UMSARS Part IV, Hoehn and Yahr (HY) Parkinson's disease staging, Schwab England Activities of Daily Living (SE ADL), and a three-point global Severity Scale (SS3). Fifty patients (male:female ratio, 1:0.9; possible MSA, 16%; probable MSA, 84%; MSA-parkinsonian, 58%; MSA-cerebellar, 42%) were assessed twice with an interval of 12.3 months. UMSARS II scores progressed by 57.3% (P Ͻ 0.0001) and UMSARS I scores by 35.6% (P Ͻ 0.0001) in relation to the respective baseline scores with no differences between motor subtypes, diagnostic categories and gender. Significant inverse correlations between (1) UM-SARS I or UMSARS II progression and (2) baseline disability measures (i.e., the respective UMSARS or SS3 scores) and disease duration were found. Furthermore, the increases in HY staging, SE ADL and SS3 correlated significantly with UMSARS I, UM-SARS II, and UMSARS IV progression. This report is the first prospective study showing rapid annual UMSARS rates of decline in MSA. Our data contribute to the ongoing validation process of UMSARS, and they facilitate the planning and implementation of future neuroprotective intervention trials.
Journal of Neurology, Neurosurgery & Psychiatry, 1990
Twenty eight patients with the clinical diagnosis of idiopathic late onset cerebellar ataxia were... more Twenty eight patients with the clinical diagnosis of idiopathic late onset cerebellar ataxia were examined clinically and by magnetic resonance imaging (MRI) or computed tomography (CT). In 298
Journal of Neurology, Neurosurgery & Psychiatry, 2001
The objective was to evaluate response rate, response duration, and toxicity after systemic and i... more The objective was to evaluate response rate, response duration, and toxicity after systemic and intraventricular chemotherapy in primary CNS lymphoma (PCNSL). From September 1995 to September 1998, 20 consecutive patients with PCNSL (median age 64, range 27 to 71 years) were enrolled in a pilot study evaluating chemotherapy without radiotherapy. A high dose methotrexate (MTX) (cycles 1, 2, 4, 5) and cytarabine (ara-C) (cycles 3, 6) based systemic therapy (including dexamethasone, vinca alkaloids, ifosfamide, and cyclophosphamide) was combined with intraventricular MTX, prednisolone, and ara-C. Complete response was achieved in 11 and partial remission in two patients; in one response could not be determined. Four patients showed progressive disease and two (70, 71 years) died from treatment related complications. Observation time was 2 to 59 months (median 31.5 months). Kaplan-Meier estimate for median time to treatment failure (TTF) was 20.5 months, and for median survival 54 months. Systemic toxicity was mainly hematological. Ommaya reservoir infection occurred in four patients and acute transient MTX induced encephalopathy in two (subacute in another). Cognitive dysfunction possibly due to treatment was seen in only one patient after relapse and after a total of 12 cycles (six at relapse). In conclusion, primary chemotherapy based on high dose MTX and ara-C is highly eYcient in PCNSL. Toxicity is manageable in patients younger than 70 years.
Neuronally differentiated P012 cells undergo synchronous apoptosis when deprived of nerve growth ... more Neuronally differentiated P012 cells undergo synchronous apoptosis when deprived of nerve growth factor (NGF). Here we show that NGF withdrawal induces actinomycin D-and cycloheximide-sensitive caspase (ICE-like) activity. The peptide inhibitor of caspase activity, N-acetyl-Asp-Glu-Val-Asp-aldehyde, was more potent than acetyl-Tyr-Val-Ala-Asp-chloromethyl ketone in preventing NGF withdrawal-induced apoptosis, suggesting an important role for caspase-3 (CPP32)-like proteases. We observed a peak of reactive oxygen species (ROS) 6 h after NGF withdrawal. ROS appear to be required for apoptosis, because cell death is prevented by the free radical spin trap, N-tert-butyl-a-phenylnitrone, and the antioxidant, N-acetylcysteine. ROS production was blocked by actinomycin D, cycloheximide, and caspase protease inhibitors, suggesting that ROS generation is downstream of new mRNA and protein synthesis and activation of caspases. Forced expression of either BCL-2 or the BCL-2-binding protein BAG-i blocked NGF withdrawal-induced apoptosis, activation of caspases, and ROS generation, showing that they function upstream of caspases. Coexpression of BCL-2 and BAG-i was more protective than expression of either protein alone.
In rats, striatal histotoxic hypoxic lesions produced by the mitochondrial toxin malonate resembl... more In rats, striatal histotoxic hypoxic lesions produced by the mitochondrial toxin malonate resemble those of focal cerebral ischemia. Intrastriatal injections of malonate induced cleavage of caspase-2 beginning at 6 h, and caspase-3-like activity as identified by DEVD biotin affinity-labeling within 12 h. DEVD affinity-labeling was prevented and lesion volume reduced in transgenic mice overexpressing BCL-2 in neuronal cells. Intrastriatal injection of the tripeptide, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk), a caspase inhibitor, at 3 h, 6 h, or 9 h after malonate injections reduced the lesion volume produced by malonate. A combination of pretreatment with the NMDA antagonist, dizocilpine (MK-801), and delayed treatment with zVAD-fmk provided synergistic protection compared with either treatment alone and extended the therapeutic window for caspase inhibition to 12 h. Treatment with cycloheximide and zVAD-fmk, but not with MK-801, blocked the malonate-induced cleavage of caspase-2. NMDA injections alone resulted in a weak caspase-2 cleavage. These results suggest that malonate toxicity induces neuronal death by more than one pathway. They strongly implicate early excitotoxicity and delayed caspase activation in neuronal loss after focal ischemic lesions and offer a new strategy for the treatment of stroke.
To evaluate proton magnetic resonance spectroscopy for detection and monitoring of upper motoneur... more To evaluate proton magnetic resonance spectroscopy for detection and monitoring of upper motoneuron degeneration in patients with amyotrophic lateral sclerosis. Methods: Seventy patients with amyotrophic lateral sclerosis according to the El Escorial criteria were compared with 48 healthy control subjects. Single-volume proton magnetic resonance spectroscopy (echo time, 272 milliseconds; repetition time, 2000 milliseconds) was performed in both motor cortices for detection of Nacetylaspartate (NAA), phosphocreatine+creatine ([P]Cr), and choline-containing compounds (Cho) to calculate the metabolite ratios NAA/Cho, NAA/(P)Cr, and Cho/ (P)Cr. In addition, absolute metabolite concentrations of NAA, (P)Cr, and Cho were obtained in 30 patients and 15 controls with the unsuppressed water signal used as an internal reference. Results: Absolute concentrations of NAA (PϽ.001) and (P)Cr (PϽ.05) were reduced in motor cortices of patients, whereas Cho concentrations remained unchanged. The NAA/Cho and NAA/(P)Cr ratios were reduced in all El Escorial subgroups (PϽ.001). The Cho/(P)Cr ratio was elevated in patients with definite amyotrophic lateral sclerosis (PϽ.05). Metabolite ratio changes corresponded to the lateralization of clinical symptoms and were weakly correlated with disease duration and disease severity. In follow-up observations of 16 patients during a mean (±SD) of 12.1±8.7 months, NAA/Cho dropped by 9.1% (PϽ.01), and Cho/(P)Cr increased by 7.0% (PϽ.01). Changes of metabolite ratios were significantly correlated with progression of disease severity. Conclusions: Measurement of NAA concentrations and NAA/Cho ratios appear to be most suitable for detection of motor cortex degeneration by singlevolume proton magnetic resonance spectroscopy. Reduced NAA/Cho ratios correspond to aspects of the clinical presentation and reflect disease progression in follow-up measurements.
Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine disorder caused by a CAG repeat expansion... more Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine disorder caused by a CAG repeat expansion in the coding region of a gene encoding ataxin-3. To study putative alterations of gene expression induced by expanded ataxin-3, we performed PCRbased cDNA subtractive hybridization in a cell culture model of SCA3. In rat mesencephalic CSM14.1 cells stably expressing expanded ataxin-3, we found a significant upregulation of mRNAs encoding the endopeptidase matrix metalloproteinase 2 (MMP-2), the transmembrane protein amyloid precursor protein, the interleukin-1 receptor-related Fos-inducible transcript, and the cytokine stromal cell-derived factor 1␣ (SDF1␣). Immunohistochemical studies of the corresponding or associated proteins in human SCA3 brain tissue confirmed these findings, showing increased expression of MMP-2 and amyloid -protein (A) in pontine neurons containing nuclear inclusions. In addition, extracellular A-immunoreactive deposits were detected in human SCA3 pons. Furthermore, pontine neurons of SCA3 brains strongly expressed the antiinflammatory interleukin-1 receptor antagonist, the proinflammatory cytokine interleukin-1, and the proinflammatory chemokine SDF1. Finally, increased numbers of reactive astrocytes and activated microglial cells were found in SCA3 pons. These results suggest that inflammatory processes are involved in the pathogenesis of SCA3.
The proto-oncogene Bcl-2 rescues cells from a wide variety of insults. Recent evidence suggests t... more The proto-oncogene Bcl-2 rescues cells from a wide variety of insults. Recent evidence suggests that Bcl-2 protects against free radicals and that it increases mitochondrial calcium-buffering capacity. The neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyride (MPTP) is thought to involve both mitochondrial dysfunction and free radical generation. We therefore investigated MPTP neurotoxicity in both Bcl-2 overexpressing mice and littermate controls. MPTP-induced depletion of dopamine and loss of [3H]mazindol binding were significantly attenuated in Bcl-2 overexpressing mice. Protection was more profound with an acute dosing regimen than with daily MPTP administration over 5 d. 1-Methyl-4-phenylpyridinium (MPP+) levels after MPTP administration were similar in Bcl-2 overexpressing mice and littermates. Bcl-2 blocked MPP+-induced activation of caspases. MPTP-induced increases in free 3-nitrotyrosine levels were blocked in Bcl-2 overexpressing mice. These results indicate that Bcl...
Prior to patent expiry of a drug, the manufacturer will generally increase marketing efforts in o... more Prior to patent expiry of a drug, the manufacturer will generally increase marketing efforts in order to maintain market-share. The introduction of generics will lead to strong competition, forcing the original patent holder to change their marketing strategy. These effects, together with other factors (e.g. governmental price legislation) may lead to increasing drug expenditures. In order to increase price competition the Dutch government plans to modernize the drug reimbursement system, which is conceived to inadequately control drug prices. In particular, drug prices may not relevantly decrease due to lack of incentives for price competition. OBJECTIVES: To investigate the magnitude of effects on market-share and drug prices, we evaluated trends in drug volume and costs after patent expiry for enalapril, fluoxetine and ranitidine in the The Netherlands. METHODS: Governmental price, volume and reimbursement policies were evaluated in order to provide a framework for developments after patent expiry. Drug use was measured as Defined Daily Doses (DDD) per 1000 population, derived from the InterAction DataBase, comprising pharmacies in the North of the The Netherlands. Drug costs were calculated per DDD. Estimated trendlines for drug costs and share of drugs in the different trade-channels (specialité, parallel, generic) were compared. RESULTS: After the patent expired, costs per DDD-for enalapril, fluoxetine and ranitidine-decreased with 61%, 51% and 69% respectively. For enalapril and fluoxetine statistical significant differences in trendlines were found. For all investigated drugs, generic products rapidly took over the majority of the market-share (over 75%). Nearly all new users received a generic drug after patent expiry. Further results will be presented on omeprazol and simvastatine, with very recent patent expiries. CONCLUSIONS: Our findings indicate that patent expiry may cause price competition leading to cost decreases. This is opposite the current opinion that the drug reimbursement system would inadequately control drug prices.
Glutathione levels are decreased in the substantia nigra of patients with Parkinson&amp;amp;#... more Glutathione levels are decreased in the substantia nigra of patients with Parkinson&amp;amp;#39;s disease. We studied whether glutathione depletion contributes to dopaminergic cell death using a specific inhibitor of glutathione biosynthesis, L-buthionine sulfoximine (BSO). We found no significant reduction of tyrosine hydroxylase-positive cells in the substantia nigra pars compacta (SNpc) when BSO was administered systemically to preweanling mice or locally to the SNpc of adult rats. However, the combination of BSO with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in preweanling mice and the combination of nigral injections of BSO with intrastriatal injections of MPP+ (1-methyl-4-phenylpyridinium), the active metabolite of MPTP in adult rats, potentiated the toxic effects of MPTP and MPP+ on nigral neurones. Our data show that glutathione depletion can result in cell death if the nigrostriatal system is metabolically compromised.
identifi ed (the Index Date was defi ned as the earliest ACE). Patients age ≥18, ≥6 months eligib... more identifi ed (the Index Date was defi ned as the earliest ACE). Patients age ≥18, ≥6 months eligibility pre-and post-Index Date, ≥1 statin fi ll and no statin augmenting fi ll 6 months before the Index Date, and ≥1 FF or SM fi ll 6 months after the Index Date (Cohort ID Period) were included. Patients with fi lls for alternative statin augmenting therapies or SCE during the Cohort ID Period were excluded. The primary outcome was SCE. Secondary outcomes were cerebrovascular event risk and eventrelated medical costs. Event risk was compared using Cox proportional hazards models, while costs were compared via generalized linear models. Multivariate analyses controlled for age, gender, geography, co-morbidities, concomitant medications, statin potency, and severity of initial ACE. RESULTS: A total of 24,625 patients added FF (n = 399) or maintained SM (n = 24,226) 6-months after initial ACE while meeting study inclusion/exclusion criteria. FF patients were younger (59 ± 10 vs. 65 ± 12, P < 0.0001), less likely female (27% vs. 34%, P = 0.002), and had shorter follow-up (358 vs. 443 days, P < 0.0001). FF patients had lower frequency of SCE (20%) vs. SM (25%), with an unadjusted hazard ratio (HR) of 0.88 (95%CI: 0.71-1.10). a similar directional trend was observed for cerebrovascular events (HR: 0.74; 95% CI: 0.40-1.37). Multivariate analyses of SCE risk demonstrated consistent directional benefi t (HR: 0.93; 95% CI: 0.74-1.16). Clinical fi ndings corresponded with 25% lower adjusted annual event-related costs compared to SM (0.75; 95% CI: 0.57-0.97; p = 0.0306). CONCLUSIONS: The positive clinical benefi ts from this real-world analysis provide evidence supporting ability of FF to reduce both SCE risk and event-related medical costs following ACE.
A common subset of genetic risk factors for Parkinson&#39;s disease (PD) and essential tremor... more A common subset of genetic risk factors for Parkinson&#39;s disease (PD) and essential tremor (ET) has been postulated. Recently, an association between the dopamine D(3) receptor (DRD3) Ser9Gly polymorphism and ET has been reported. We studied whether PD tremor is influenced by Ser9Gly in a genetic association study based on the gene bank of the German Competence Network on Parkinson&#39;s disease. The study included analyses of motor predominance (mixed, hypokinetic, and tremor), and tremor type (resting, postural, and action). We did not identify any effect of DRD3 Ser9Gly on tremor in PD, even when regarding various symptom combinations to avoid missing a weak effect on the phenotype. Additional studies incorporating symptoms at disease onset, and grading of tremor response to dopaminergic therapy, are warranted.
Nitrous oxide has multiple deleterious effects on cobalamin metabolism and causes decreases in ac... more Nitrous oxide has multiple deleterious effects on cobalamin metabolism and causes decreases in activities of both mammalian cobalamin dependent enzymes in rats. J Clin Invest 1981;67:1270-1283. 24. Carmel R, Karnaze DS, Weiner JM. Neurologic abnormalities in cobalamin deficiency are associated with higher cobalamin "analogue" values than are haematological abnormalities.
Figure. 18 F-fluorodeoxyglucose (FDG) PET during a relapse after withdrawal of methotrexate. FDG ... more Figure. 18 F-fluorodeoxyglucose (FDG) PET during a relapse after withdrawal of methotrexate. FDG uptake is enhanced in the right caput nuclei caudati (CNC) as compared with the contralateral side. Regions of interest in this plane revealed maximal standard uptake values of 6.3 (right CNC) and 5.8 (left CNC).
Objective: Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), known as atypi... more Objective: Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), known as atypical parkinsonian syndromes (APS), are neurodegenerative disorders with severe disability and decreased life expectancy. Little is known about the health-related quality of life (HrQoL) and its determinants in patients with those disorders. The objective of our cross-sectional study was to evaluate the HrQoL in patients with APS and to identify the determinants of HrQoL. Methods: A total of 101 consecutive patients with MSA (n = 54) and PSP (n = 47) were recruited in four German neurological centers. Disease severity was assessed using the Hoehn and Yahr stages and the Unified MSA Rating Scale. The HrQoL was evaluated using the EuroQol instrument (EQ-5D and EQ-VAS). Independent determinants of HrQoL were identified in multiple regression analyses. Results: The mean EQ-VAS score was 52% lower than that reported for the general population (36.9 ± 18.3 vs. 77.4 ± 19.0). Of the study particip...
The disease-specific Unified Multiple System Atrophy Rating Scale (UMSARS) has been developed rec... more The disease-specific Unified Multiple System Atrophy Rating Scale (UMSARS) has been developed recently and validated for assessing disease severity in multiple system atrophy (MSA). Here, we aimed at (1) assessing rates of disease progression in MSA and (2) validating UMSARS for sensitivity to change over time. Impairment was assessed at two time points 12 months apart using UMSARS Part I (historical review), UMSARS Part II (motor examination), as well as measures of global disease severity, including UMSARS Part IV, Hoehn and Yahr (HY) Parkinson's disease staging, Schwab England Activities of Daily Living (SE ADL), and a three-point global Severity Scale (SS3). Fifty patients (male:female ratio, 1:0.9; possible MSA, 16%; probable MSA, 84%; MSA-parkinsonian, 58%; MSA-cerebellar, 42%) were assessed twice with an interval of 12.3 months. UMSARS II scores progressed by 57.3% (P Ͻ 0.0001) and UMSARS I scores by 35.6% (P Ͻ 0.0001) in relation to the respective baseline scores with no differences between motor subtypes, diagnostic categories and gender. Significant inverse correlations between (1) UM-SARS I or UMSARS II progression and (2) baseline disability measures (i.e., the respective UMSARS or SS3 scores) and disease duration were found. Furthermore, the increases in HY staging, SE ADL and SS3 correlated significantly with UMSARS I, UM-SARS II, and UMSARS IV progression. This report is the first prospective study showing rapid annual UMSARS rates of decline in MSA. Our data contribute to the ongoing validation process of UMSARS, and they facilitate the planning and implementation of future neuroprotective intervention trials.
Journal of Neurology, Neurosurgery & Psychiatry, 1990
Twenty eight patients with the clinical diagnosis of idiopathic late onset cerebellar ataxia were... more Twenty eight patients with the clinical diagnosis of idiopathic late onset cerebellar ataxia were examined clinically and by magnetic resonance imaging (MRI) or computed tomography (CT). In 298
Journal of Neurology, Neurosurgery & Psychiatry, 2001
The objective was to evaluate response rate, response duration, and toxicity after systemic and i... more The objective was to evaluate response rate, response duration, and toxicity after systemic and intraventricular chemotherapy in primary CNS lymphoma (PCNSL). From September 1995 to September 1998, 20 consecutive patients with PCNSL (median age 64, range 27 to 71 years) were enrolled in a pilot study evaluating chemotherapy without radiotherapy. A high dose methotrexate (MTX) (cycles 1, 2, 4, 5) and cytarabine (ara-C) (cycles 3, 6) based systemic therapy (including dexamethasone, vinca alkaloids, ifosfamide, and cyclophosphamide) was combined with intraventricular MTX, prednisolone, and ara-C. Complete response was achieved in 11 and partial remission in two patients; in one response could not be determined. Four patients showed progressive disease and two (70, 71 years) died from treatment related complications. Observation time was 2 to 59 months (median 31.5 months). Kaplan-Meier estimate for median time to treatment failure (TTF) was 20.5 months, and for median survival 54 months. Systemic toxicity was mainly hematological. Ommaya reservoir infection occurred in four patients and acute transient MTX induced encephalopathy in two (subacute in another). Cognitive dysfunction possibly due to treatment was seen in only one patient after relapse and after a total of 12 cycles (six at relapse). In conclusion, primary chemotherapy based on high dose MTX and ara-C is highly eYcient in PCNSL. Toxicity is manageable in patients younger than 70 years.
Neuronally differentiated P012 cells undergo synchronous apoptosis when deprived of nerve growth ... more Neuronally differentiated P012 cells undergo synchronous apoptosis when deprived of nerve growth factor (NGF). Here we show that NGF withdrawal induces actinomycin D-and cycloheximide-sensitive caspase (ICE-like) activity. The peptide inhibitor of caspase activity, N-acetyl-Asp-Glu-Val-Asp-aldehyde, was more potent than acetyl-Tyr-Val-Ala-Asp-chloromethyl ketone in preventing NGF withdrawal-induced apoptosis, suggesting an important role for caspase-3 (CPP32)-like proteases. We observed a peak of reactive oxygen species (ROS) 6 h after NGF withdrawal. ROS appear to be required for apoptosis, because cell death is prevented by the free radical spin trap, N-tert-butyl-a-phenylnitrone, and the antioxidant, N-acetylcysteine. ROS production was blocked by actinomycin D, cycloheximide, and caspase protease inhibitors, suggesting that ROS generation is downstream of new mRNA and protein synthesis and activation of caspases. Forced expression of either BCL-2 or the BCL-2-binding protein BAG-i blocked NGF withdrawal-induced apoptosis, activation of caspases, and ROS generation, showing that they function upstream of caspases. Coexpression of BCL-2 and BAG-i was more protective than expression of either protein alone.
In rats, striatal histotoxic hypoxic lesions produced by the mitochondrial toxin malonate resembl... more In rats, striatal histotoxic hypoxic lesions produced by the mitochondrial toxin malonate resemble those of focal cerebral ischemia. Intrastriatal injections of malonate induced cleavage of caspase-2 beginning at 6 h, and caspase-3-like activity as identified by DEVD biotin affinity-labeling within 12 h. DEVD affinity-labeling was prevented and lesion volume reduced in transgenic mice overexpressing BCL-2 in neuronal cells. Intrastriatal injection of the tripeptide, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk), a caspase inhibitor, at 3 h, 6 h, or 9 h after malonate injections reduced the lesion volume produced by malonate. A combination of pretreatment with the NMDA antagonist, dizocilpine (MK-801), and delayed treatment with zVAD-fmk provided synergistic protection compared with either treatment alone and extended the therapeutic window for caspase inhibition to 12 h. Treatment with cycloheximide and zVAD-fmk, but not with MK-801, blocked the malonate-induced cleavage of caspase-2. NMDA injections alone resulted in a weak caspase-2 cleavage. These results suggest that malonate toxicity induces neuronal death by more than one pathway. They strongly implicate early excitotoxicity and delayed caspase activation in neuronal loss after focal ischemic lesions and offer a new strategy for the treatment of stroke.
To evaluate proton magnetic resonance spectroscopy for detection and monitoring of upper motoneur... more To evaluate proton magnetic resonance spectroscopy for detection and monitoring of upper motoneuron degeneration in patients with amyotrophic lateral sclerosis. Methods: Seventy patients with amyotrophic lateral sclerosis according to the El Escorial criteria were compared with 48 healthy control subjects. Single-volume proton magnetic resonance spectroscopy (echo time, 272 milliseconds; repetition time, 2000 milliseconds) was performed in both motor cortices for detection of Nacetylaspartate (NAA), phosphocreatine+creatine ([P]Cr), and choline-containing compounds (Cho) to calculate the metabolite ratios NAA/Cho, NAA/(P)Cr, and Cho/ (P)Cr. In addition, absolute metabolite concentrations of NAA, (P)Cr, and Cho were obtained in 30 patients and 15 controls with the unsuppressed water signal used as an internal reference. Results: Absolute concentrations of NAA (PϽ.001) and (P)Cr (PϽ.05) were reduced in motor cortices of patients, whereas Cho concentrations remained unchanged. The NAA/Cho and NAA/(P)Cr ratios were reduced in all El Escorial subgroups (PϽ.001). The Cho/(P)Cr ratio was elevated in patients with definite amyotrophic lateral sclerosis (PϽ.05). Metabolite ratio changes corresponded to the lateralization of clinical symptoms and were weakly correlated with disease duration and disease severity. In follow-up observations of 16 patients during a mean (±SD) of 12.1±8.7 months, NAA/Cho dropped by 9.1% (PϽ.01), and Cho/(P)Cr increased by 7.0% (PϽ.01). Changes of metabolite ratios were significantly correlated with progression of disease severity. Conclusions: Measurement of NAA concentrations and NAA/Cho ratios appear to be most suitable for detection of motor cortex degeneration by singlevolume proton magnetic resonance spectroscopy. Reduced NAA/Cho ratios correspond to aspects of the clinical presentation and reflect disease progression in follow-up measurements.
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Papers by T. Klockgether