Epidemiology of early-onset Parkinson's disease in Finland.

OBJECTIVE: The contribution of genetic causes to Parkinson's disease (PD) is strongest in early-onset cases. We ascertained a nationwide cohort of patients in order to study the genetic epidemiology of early-onset PD (EOPD) in Finland. METHODS: By means of a search in a national database we ascertained all patients with EOPD. These patients had become eligible for reimbursement of PD drugs between the years 1995-2006 and were <55 years of age at the time of PD diagnosis. A total of 441 patients consented and provided clinical and genealogical information. RESULTS: The incidence of EOPD increased 1.7-fold between the years 1995-2006, the mean annual incidence being 3.3/100,000. Fifty-two patients (11.8%) reported an affected first-degree relative. The birthplaces of patients with PD among first-degree relatives were clustered in certain regions in the southwestern and western coastal provinces of Finland and in the eastern province of Savo. Furthermore, the distance between the birthplaces of the patients' parents was smaller for patients, who had first-degree relatives with PD than for patients with no family history of PD. CONCLUSIONS: Our data suggest that the incidence of EOPD is increasing. The birthplaces of patients with PD among first-degree relatives were clustered in certain provinces of Finland suggesting that monogenic forms of PD or genetic susceptibility of PD are present in the population.

Trends in treatment and outcome of stroke patients in Finland from 1999 to 2007. PERFECT Stroke, a nationwide register study.

INTRODUCTION: This article in this supplement issue on the Performance, Effectiveness, and Costs of Treatment episodes (PERFECT) project describes trends in Finnish stroke treatment and outcome. MATERIAL AND METHODS: The PERFECT Stroke study uses multiple national registry linkages at individual patient level to produce a national stroke database with comprehensive follow-up of all hospital-treated stroke patients in Finland. RESULTS: There were 94,316 incident stroke patients treated in Finnish hospitals from 1999 to 2007. Lengths-of-stays decreased after ischemic stroke (IS), and increased after intracerebral (ICH) and subarachnoid (SAH) hemorrhage. Ten-year survival improved in IS (hazard ratio 0.75; 95% CI 0.71-0.79) and ICH patients (0.88; 0.79-0.97), increasing median survival by 2 and 1 life-years respectively. This has translated into more days spent home among IS patients, but not among ICH patients. Treatment by neurologists improved the survival of IS (odds ratio [OR] 1.77; 95% CI 1.70-1.84) and ICH patients (OR 1.55; 95% CI 1.40-1.69), and treatment by neurosurgeons of SAH patients (OR 2.66; 95% CI 2.25-3.16), the effects were further improved by care in specialized stroke centers. DISCUSSION: The survival of Finnish IS and ICH patients has improved. Specialized acute care was associated with improved outcome.

Direct costs of patients with stroke can be continuously monitored on a national level: performance, effectiveness, and Costs of Treatment episodes in Stroke (PERFECT Stroke) Database in Finland.

BACKGROUND AND PURPOSE: Treatment of stroke consumes a significant portion of all healthcare expenditure. We developed a system for monitoring costs from individual patient data on a national level in Finland. METHODS: Multiple national administrative registers were linked to gain episode-of-care data on all hospital-treated patients with incident stroke over the years 1999 to 2007 (n = 94,316). Inpatient and specialist outpatient costs were evaluated with a cost database, long-term care costs with fixed prices, and medication costs with true retail prices. RESULTS: For the patients of Year 2007, the mean 1-year costs after an ischemic stroke were $29 580, after an intracerebral hemorrhage $36,220, and after a subarachnoid hemorrhage $42,570, valued in Year 2008 U.S. dollars. Only part of these costs are attributable to stroke, because the annual costs prior to stroke were significant, $8900 before ischemic stroke, $7600 before intracerebral hemorrhage, and $4200 before subarachnoid hemorrhage. Older patients with ischemic stroke, and, among patients with ischemic stroke and subarachnoid hemorrhage, women, incurred higher costs. The mean estimated lifetime costs were $130,000 after ischemic stroke or intracerebral hemorrhage and $80,000 after subarachnoid hemorrhage. Annually $1.6 billion is spent in the care of Finnish patients with stroke, which equals to 7% of the national healthcare expenditure, or 0.6% of the gross domestic product. Costs of patients with stroke are increasing with prolonged survival and the aging population. CONCLUSIONS: Treatment of patients with stroke is a large national investment. Setting up a nationwide system for continuous monitoring of stroke costs is feasible. Cost data should optimally be evaluated in conjunction with effectiveness and performance indicators.

Stroke monitoring on a national level: PERFECT Stroke, a comprehensive, registry-linkage stroke database in Finland.

BACKGROUND AND PURPOSE: Stroke databases are established to systematically evaluate both the treatment and outcome of stroke patients and the structure and processes of stroke services. Comprehensive data collection on this common disease is resource-intensive, and national stroke databases often include only patients from selected hospitals. Here we describe an alternative national stroke database. METHODS: We established a nationwide stroke database with multiple administrative registry linkages at the individual-patient level. Information on comorbidities; treatments before, during, and after stroke; living status; recurrences; case fatality; and costs were collected for each hospital-treated stroke patient. RESULTS: The current database includes 94 316 patients with incident stroke between January 1999 and December 2007, with follow-up until December 2008. Annually, 10 500 new patients are being added. One-year recurrence was 13% and case fatality was 27% during the study period. In 2007, 86% of patients survived 1 month and 77% were living at home at 3 months, but the proportion treated in stroke centers (62%) or with nationally recommended secondary preventive medication after ischemic stroke (49%) was still suboptimal. CONCLUSIONS: In comparison with other national stroke databases, our method enables higher coverage and more thorough follow-up of patients. Information on long-term recurrences, case fatality, or costs is not often included in national stroke databases. Our database has low maintenance costs, but it lacks detailed data on in-hospital processes. Use of national administrative data, where such linkage is possible, saves resources, achieves high rates of long-term follow-up, and allows for comprehensive monitoring of the burden of the disease.

Effectiveness of primary and comprehensive stroke centers: PERFECT stroke: a nationwide observational study from Finland.

BACKGROUND AND PURPOSE: Previous studies show better outcomes for patients with stroke receiving care in stroke units, but many different stroke unit criteria have been published. In this study, we explored whether stroke centers fulfilling standardized Brain Attack Coalition criteria produce better patient outcomes than hospitals without stroke centers. METHODS: We did an observational register-linkage study of all patients with ischemic stroke treated in Finland between 1999 and 2006. After exclusion of recurrent strokes and nonanalyzable patients, we included 61 685 consecutive patients treated in 333 hospitals classified in national audits either as Comprehensive Stroke Centers, Primary Stroke Centers, or General Hospitals according to Brain Attack Coalition criteria. Primary outcome measures were case-fatality and being in institutional care 1 year after stroke. RESULTS: Care in stroke centers was associated with lower 1-year case-fatality and reduced institutional care compared with General Hospitals. The number-needed-to-treat to prevent 1 death or institutional care at 1 year was 29 for Comprehensive Stroke Centers and 40 for Primary Stroke Centers versus General Hospitals. Patients treated in stroke centers had lower mortality during the entire follow-up of up to 9 years and their median survival was increased by 1 year. CONCLUSIONS: This study shows a clear association between the level of acute stroke care and patient outcome and supports use of published criteria for primary and comprehensive stroke centers.

Carbon monoxide poisoning-induced nigrostriatal dopaminergic dysfunction detected using positron emission tomography (PET).

A malfunctioning heater caused a severe carbon monoxide (CO) intoxication leading to unconsciousness and predominantly right-sided extrapyramidal syndrome in a 29-year-old man. Follow-up included thorough clinical monitoring, and brain MRI and PET studies. Nine days after the poisoning, brain MRI showed symmetrical necrosis in the globus pallidi, but no abnormality was found in the substantia nigra. In addition, white matter periventricular lesions were seen. In a control scan 14 months later the white matter changes had subsided but small necrotic lesions were still noted bilaterally in the globus pallidi. A 6-[(18)F]fluoro-L-dopa PET examination performed 5 weeks after the intoxication revealed impaired presynaptic dopaminergic function in the left putamen whereas in the right putamen the dopaminergic activity was within normal limits. [(11)C] raclopride PET imaging 4 months after the poisoning showed no abnormality in postsynaptic D2 binding in the striatum. Clinically, the parkinsonian symptoms resolved 1.5 years after the poisoning. The final outcome of the recovery was excellent, and the patient returned to work. This is the first case reported where unilateral presynaptic, dopaminergic hypofunction in putamen could be confirmed with fluoro-l-dopa PET imaging on a patient with extrapyramidal syndrome caused by CO poisoning. Our results emphasize that CO intoxication can lead to striatal dopaminergic hypofunction, and that PET is a sensitive tool in evaluating extrapyramidal system after sudden neurotoxic insult.

Working capacity and cervical dystonia.

The objective of this questionnaire study was to assess the effect of cervical dystonia on patients' working capacity. Of the 303 working-aged members of the Finnish Dystonia Association (N = 433) who participated in the study 247 (82%) had cervical dystonia. Their median age was 50 years, the median duration of CD symptoms was 12.3 years. Most (78%) subjects were on botulinum toxin treatment. Ninety-seven (39%) had retired because of CD at a median age of 48 years; 96 (39%) of the subjects were working: 87 full-time and 9 part-time. The remaining participants were on sick leave, unemployed, studying or retired of other reasons. Retirement occurred more than ten years earlier compared with the general Finnish population. All possibilities to help CD patients to continue longer in work should be considered early.

T2-weighted high-intensity signals in the basal ganglia as an interesting image finding in Unverricht-Lundborg disease.

We conducted a search for white matter changes (WMCs) in 13 Unverricht-Lundborg disease patients and compared the prevalence of WMCs in these patients to age-matched long-term epileptics and healthy controls. ULD patients had significantly more T2-weighted high-intensity signals on MRI than control subjects, due to the increased prevalence of these signals in the basal ganglia. Interestingly, ULD patients with the basal ganglia changes were overweight. Basal ganglia T2-weighted high-intensity signals are novel findings in ULD.

A follow-up study on 6-[18F]fluoro-L-dopa uptake in early Parkinson's disease shows nonlinear progression in the putamen.

Sixteen subjects with de novo Parkinson's disease (PD) underwent three 6-[18F]fluoro-L-dopa (Fdopa) positron emission tomography (PET) scans during a follow-up time of 5 years (mean +/- SD 5.5 +/- 0.4 years) to study the progression of striatal dopaminergic hypofunction. Throughout the study, the smallest Fdopa uptake values were found in the dorso-caudal part of the putamen contralateral to the side with dominant motor symptoms. The rate of decline in Fdopa uptake in the contralateral putamen was faster in the beginning of the disease and slowed down as the disease progressed. The annual decline in Fdopa influx constant (Ki, unit x 10(-3) min(-1)) was on average 0.5 during the first 2 years and 0.2 during the subsequent 3 years (P = 0.002) in the contralateral putamen. In caudate, the rate of decline in Fdopa values was slower than in the putamen and did not change significantly during the follow-up time, annual decline in the contralateral caudate being 0.1 between baseline and 2 years and 0.3 between 2 and 5 years (P = 0.4). These results suggest that progression of putaminal dopaminergic hypofuncion in PD follows a nonlinear pattern at least in the contralateral side being faster in the beginning of the disease.

Comparison of pharmacokinetic profile of levodopa throughout the day between levodopa/carbidopa/entacapone and levodopa/carbidopa when administered four or five times daily.

OBJECTIVES: To compare plasma levodopa concentrations after repeated doses of levodopa/carbidopa/entacapone (LCE) and levodopa/carbidopa (LC). METHODS: Open-label, randomized, two-period, active-controlled, cross-over study with four dosing regimens: groups I and II (healthy volunteers and Parkinson's disease patients) received levodopa 100 mg or 150 mg four times daily, respectively, and groups III and IV (healthy volunteers) received the same strengths of levodopa five times daily. Pharmacokinetic (PK) parameters determined for levodopa included Cmin, Cmax, Cmax - Cmin, AUC, t(1/2), and tmax. RESULTS: In healthy volunteers and PD patients, mean trough levels (Cmin), Cmax, and AUC of levodopa were, in general, significantly higher during LCE compared to LC administration. Compared to Cmin, Cmax, and AUC, differences between the treatments in variability of levodopa concentrations (Cmax - Cmin) were less consistent. CONCLUSIONS: The present results on the differences in levodopa PK between LCE and LC provide a basis to evaluate the relationship of levodopa PK and the induction of motor complications in an on-going study in early Parkinson's disease using similar dosing regimens.

Neurological symptoms and natural course of xeroderma pigmentosum.

We have prospectively followed 16 Finnish xeroderma pigmentosum (XP) patients for up to 23 years. Seven patients were assigned by complementation analysis to the group XP-A, two patients to the XP-C group and one patient to the XP-G group. Six of the seven XP-A patients had the identical mutation (Arg228Ter) and the seventh patient had a different mutation (G283A). Further patients were assigned to complementation groups on the basis of their consanguinity to an XP patient with a known complementation group. The first sign of the disease in all the cases was severe sunburn with minimal sun exposure in early infancy. However, at the time the diagnosis was made in only two cases. The XP-A patients developed neurological and cognitive dysfunction in childhood. The neurological disease advanced in an orderly fashion through its successive stages, finally affecting the whole nervous system and leading to death before the age of 40 years. Dermatological and ocular damage of the XP-A patients tended to be limited. The two XP-C patients were neurologically and cognitively intact despite mild brain atrophy as seen by neuroimaging. The XP-G patients had sensorineural hearing loss, laryngeal dystonia and peripheral neuropathy. The XP-C patients had severe skin and ocular malignancies that first presented at pre-school age. They also showed immunosuppression in cell-mediated immunity. Neurological disease appears to be associated with the complementation group and the failure of fibroblasts to recover RNA synthesis following UV irradiation, but not necessarily to the severity of the dermatological symptoms, the hypersensitivity of fibroblasts to UVB killing or the susceptibility of keratinocytes to UVB-induced apoptosis.

Methanol intoxication-induced nigrostriatal dysfunction detected using 6-[18F]fluoro-L-dopa PET.

Ingestion of windshield washer liquid resulted with an acute severe methanol intoxication in a 49-year old man. He developed optic atrophy with blindness, and an extrapyramidal syndrome. Putaminal injury and hyperintensity in the subcortical white matter was seen in a brain MRI. PET scanning with 6-[18F]fluoro-L-dopa confirmed symmetrical impaired presynaptic dopaminergic activity in the striatum, indicative of functional impairment of dopaminergic nigrostriatal neurons. The striatal uptake was more markedly impaired in the putamina (40% of controls) than in the caudate nuclei (60% of controls). To our knowledge, this is the first report of an 18F-dopa PET scanning result in a case of an acute methanol poisoning.

Geographical variation of medicated parkinsonism in Finland during 1995 to 2000.

We performed a nation-wide study on geographical variation in the incidence and prevalence of medicated parkinsonism among the Finns aged > or =30 years using Bayesian spatial conditional autoregressive models. Registry of reimbursed medication for parkinsonism and a prescription database of purchase of these drugs were used to identify the study subjects. They were located by the map coordinates of the place of residence and aggregated into regular 100 km(2) grid cells. A total of 7,190 incident and 10,616 prevalent cases were found. The age-adjusted annual incidence was 32.6/100,000 (95% HDR 31.8-33.4) during the years 1995 to 2000 and prevalence was 268/100,000 (95% HDR 263-274) in 2000. The male to female ratio was 1.45 (95% HDR 1.39-1.51) in incidence and 1.54 (95% HDR 1.47-1.61) in prevalence. There was strong evidence for geographic variation in incidence and prevalence. A zone with high incidence and prevalence was identified in the eastern and central part of Finland. There was no evidence for difference in incidence and prevalence between urban and rural areas. The marked (more than two-fold) geographic variation can hardly be caused solely by practices of the registration and collection of data on diagnosis or by methodological issues, but rather suggests to geographic variation in protective and predisposing factors of Parkinsonism in Finland.

Transoesophageal echocardiography should be considered in patients with ischaemic stroke or transient ischaemic attack.

BACKGROUND AND PURPOSE: In this present study, we tried to find out if there is a subgroup of patients that should not undergo transoesophageal echocardiography (TEE) after an ischaemic stroke or transient ischaemic attack (TIA). METHODS: A total of 441 consecutive unselected patients with ischaemic stroke or TIA suitable for anticoagulation were examined with TEE in the acute phase. The patients were divided into five subcategories according to their rhythm, age and the findings in carotid sonography, and into two groups according to the presence of clinical risk factors for ischaemic stroke or TIA. RESULTS: From the 441 studied patients, 60 (14%) had chronic or paroxysmal atrial fibrillation (AF) and 381 (86%) were in sinus rhythm (SR). Of the patients in SR, 46 (12%) were below 50 years old. The carotid sonography was conducted in 240 patients above 50 years old and in SR, and <50% internal carotid artery (ICA) stenosis was found in 194 (81%) patients and > or =50% ICA in 46 (19%) patients. Potential cardiac sources of embolism were found in patients both with AF or in SR (70% versus 46%), both below and above 50-year-old patients in SR (37% versus 47%), both in over 50-year-old patients in SR with <50% ICA stenosis and > or =50% ICA stenosis (41% versus 61%) and in patients in SR either without or with clinical risk factors for ischaemic stroke or TIA (43% versus 51%). On the basis of the TEE study, oral anticoagulation was started in 36 (9%) patients in SR. CONCLUSION: These results support TEE in patients with ischaemic stroke or TIA who are candidates for receiving oral anticoagulation.

Early recovery and functional outcome are related with causal stroke subtype: data from the tinzaparin in acute ischemic stroke trial.

INTRODUCTION: Baseline severity and causal subtype are predictors of outcome in ischemic stroke. We used data from the Tinzaparin in Acute Ischemic Stroke Trial (TAIST) to further assess the relationship among stroke subtype, early recovery, and outcome. METHODS: Patients with ischemic stroke (<48 hours ictus) and enrolled into TAIST were included. Severity was measured prospectively as the Scandinavian Neurological Stroke Scale (SNSS) at days 0, 4, 7, and 10. Causal subtype as large artery atherosclerosis (LAA), cardioembolism (CE), or small vessel occlusion (SVO) was assigned after standard investigations. The rate of recovery was calculated as the change in SNSS at each time point. Functional outcome was assessed using the modified Rankin Scale (mRS) and Barthel Index at day 90. RESULTS: Analyses were performed on the 1190 patients in TAIST who met criteria for LAA, CE, and SVO. The largest change in SNSS score occurred between baseline and day 4 and was greatest in SVO (median improvement 4 U), compared with LAA (median improvement 2 U) and CE (median improvement 2 U) (P < .0001). If no improvement in SNSS had occurred by day 4, irrespective of subgroup, then early recovery (median SNSS improvement by day 10: 2) and functional outcome (mRS 4) tended to be limited; patients who recovered early tended to continue to improve (median SNSS improvement by day 10: 11) and had a better outcome at day 90 (median, mRS 2). CONCLUSIONS: Recovery is related to causal subtype. In all subtypes most recovery occurred by day 4, and was predictive of longer-term functional outcome.

Substantial thalamostriatal dopaminergic defect in Unverricht-Lundborg disease.

PURPOSE: Unverricht-Lundborg disease (ULD) is currently classified as progressive myoclonus epilepsy. Myoclonus, the characteristic symptom in ULD, suggests that dopamine neurotransmission may be involved in the pathophysiology of ULD. Our purpose was to examine brain dopaminergic function in ULD patients. METHODS: Four genetically and clinically diagnosed ULD patients and eight healthy controls were scanned with [(11)C]raclopride-PET. PET images were coregistered to individual 1.5 T MR images and region-of-interest analysis was performed for the striatum and thalamus. Standardized uptake values and individual voxel-wise binding potential maps of the patients and controls were also analyzed. RESULTS: ULD patients had markedly higher (31-54%) dopamine D2-like receptor availabilities than healthy controls in both the striatum and the thalamus. The proportionally highest binding potentials were detected in the thalamus. There were no significant differences in the cerebellar uptake of [(11)C]raclopride in ULD patients versus healthy controls. Voxel-based results were in accordance with the region-of-interest analysis. CONCLUSIONS: These results suggest that dopaminergic modulation at the level of the striatum and thalamus could be a crucial factor contributing to the symptoms of ULD. In the light of our data, we propose that ULD with dopamine dysfunction and dyskinetic symptoms shares certain pathophysiological mechanisms with classical movement disorders. Future studies are therefore warranted to study the effect of dopaminergic pharmacotherapy in ULD.

Stroke severity, early recovery and outcome are each related with clinical classification of stroke: data from the 'Tinzaparin in Acute Ischaemic Stroke Trial' (TAIST).

INTRODUCTION: Baseline severity and clinical stroke syndrome (Oxford Community Stroke Project, OCSP) classification are predictors of outcome in stroke. We used data from the 'Tinzaparin in Acute Ischaemic Stroke Trial' (TAIST) to assess the relationship between stroke severity, early recovery, outcome and OCSP syndrome. METHODS: TAIST was a randomised controlled trial assessing the safety and efficacy of tinzaparin versus aspirin in 1484 patients with acute ischaemic stroke. Severity was measured as the Scandinavian Neurological Stroke Scale (SNSS) at baseline and days 4, 7 and 10, and baseline OCSP clinical classification recorded: total anterior circulation infarct (TACI), partial anterior circulation infarct (PACI), lacunar infarct (LACI) and posterior circulation infarction (POCI). Recovery was calculated as change in SNSS from baseline at day 4 and 10. The relationship between stroke syndrome and SNSS at days 4 and 10, and outcome (modified Rankin Scale at 90 days) were assessed. RESULTS: Stroke severity was significantly different between TACI (most severe) and LACI (mildest) at all four time points (p<0.001), with no difference between PACI and POCI. The largest change in SNSS score occurred between baseline and day 4; improvement was least in TACI (median 2 units), compared to other groups (median 3 units) (p<0.001). If SNSS did not improve by day 4, then early recovery and late functional outcome tended to be limited irrespective of clinical syndrome (SNSS, baseline: 31, day 10: 32; mRS, day 90: 4); patients who recovered early tended to continue to improve and had better functional outcome irrespective of syndrome (SNSS, baseline: 35, day 10: 50; mRS, day 90: 2). CONCLUSIONS: Although functional outcome is related to baseline clinical syndrome (best with LACI, worst with TACI), patients who improve early have a more favourable functional outcome, irrespective of their OCSP syndrome. Hence, patients with a TACI syndrome may still achieve a reasonable outcome if early recovery occurs.

Parkinson's disease and working capacity.

The purpose of the present study was to establish how Parkinson's disease (PD) affects working capacity. Altogether, 937 (70%) of 1,343 working-aged members of the Finnish Parkinson Association participated in a questionnaire study. The ages of the subjects were between 29 and 65 years, median 59.0 years; 508 (54%) were men. The median (quartile range) duration of PD symptoms was 7.3 (4.3-11.3) years, and the median self-estimated severity of the disease on the Hoehn & Yahr scale was 2. Only 150 of 937 subjects (16%) were still working: 112 (12%) full-time and 38 (4%) part-time. Among those 343 (37%) who had retired purely because of PD at a median age of 53.4 years, the median working time was 1.7 years after established diagnosis. In part-time work, PD patients had been able to continue for a median of 4.3 years. PD often leads to early retirement; compared with the general Finnish population of similar age, PD patients had retired on the average 6 years earlier. Young age, mild symptoms, and short duration of the disease as well as adjustments enabling easier employment were associated with the possibility to continue longer in the work force.

Carotid sonography and transesophageal echocardiography in patients with ischemic stroke or transient ischemic attack in the territory of the carotid artery.

PURPOSE: To assess the benefit of combining carotid sonography and transesophageal echocardiography (TEE) for the evaluation of patients with stroke or transient ischemic attack (TIA) in the territory of the carotid artery. METHODS: During a 2-year period in Turku University Hospital, consecutive in patients with stroke or TIA who were candidates for carotid endarterectomy and for oral anticoagulation were evaluated with carotid sonography for symptomatic moderate (50-69%) or severe (>or=70%) internal carotid artery (ICA) stenosis, and with TEE for potential cardiac sources of embolism. RESULTS: In 20% (40/197) of patients, a severe symptomatic ICA stenosis and/or a major risk factor for a cardiac source of embolism were found. In 56% (110/197) of patients, a moderate or severe symptomatic ICA stenosis and/or a potential cardiac source of embolism were found, whereas 11% (21/197) of patients had both a moderate or severe symptomatic ICA stenosis and a potential cardiac source of embolism. CONCLUSIONS: This study suggests that the presence of a moderate or severe symptomatic ICA stenosis does not exclude the presence of a potential cardiac source of embolism and vice versa. Carotid sonography and TEE complement each other and are valuable diagnostic tools that should be recommended in patients with ischemic stroke or TIA in the territory of the carotid artery when they are candidates for carotid endarterectomy and for oral anticoagulation.