Dynamically Weighted Hidden Markov Model for Spam Deobfuscation Seunghak Lee Iryoung Jeong Seungjin Choi Abstract and its effect is limited. Other approaches involve varioussearch strategies. The Viterbi decoding is a time-consumingSpam deobfuscation is a processing to detect obfus-task for HMMs which contain a large vocabulary (e.g., 20,000cated words appeared in spam emails and
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Za200504000544.pdf20. Nisbet AP, Foster OJ, Kingsbury A, Eve DJ, Daniel SE, Marsden 40. Berkowitz BA. The relationship of pharmokinetics to pharmaco- CD, Lees AJ. Preproenkephalin and preprotachykinin messenger logical activity, morphine, methadone and naloxone. Clin Pharma- RNA expression in normal human basal ganglia and in Parkinson’s disease. Neuroscience 1995;66:361–376.
41. Ngai SH, Berkowitz BA, Yang JC, Hempstead J, Spector S. Pharma- 21. Calon F, Birdi S, Rajput AH, Hornykiewicz O, Bedard PJ, Di PT.
cokinetics of naloxone in rats and in man: basis for its potency and Increase of preproenkephalin mRNA levels in the putamen of short duration of action. Anesthesiology 1976;44:398 – 401.
Parkinson disease patients with levodopa-induced dyskinesias.
42. Manson AJ, Schrag A, Lees AJ. Low-dose olanzapine for levodopa J Neuropathol Exp Neurol 2002;61:186 –196.
induced dyskinesias. Neurology 2000;55:795–799.
22. Piccini P, Weeks RA, Brooks DJ. Alterations in opioid receptor 43. Sieradzan KA, Fox SH, Hill M, Dick J, Crossman AR, Brotchie binding in Parkinson’s disease patients with levodopa-induced JM. Cannabinoids reduce levodopa-induced dyskinesia in Parkin- dyskinesia. Ann Neurol 1997;42:720 –726.
son’s disease: a pilot study. Neurology 2001;57:2108 –2111.
23. Henry B, Fox SH, Crossman AR, Brotchie JM. - and ␦-Opioid 44. Rascol O, Nutt JG, Blin O, et al. Induction by dopamine D1 receptor antagonists reduce levodopa-induced dyskinesia in the receptor agonist ABT-431 of dyskinesia similar to levodopa in MPTP-lesioned primate model of Parkinson’s disease. Exp Neurol patients with Parkinson disease. Arch Neurol 2001;58:249 –254.
45. Rascol O, Arnulf I, Peyro-Saint Paul H, et al. Idazoxan, an alpha-2 24. Klintenberg R, Svenningsson P, Gunne L, Andre´n PE. Naloxone antagonist, and L-DOPA-induced dyskinesias in patients with Par- reduces levodopa-induced dyskinesias and apomorphine-induced kinson’s disease. Mov Disord 2001;16:708 –713.
rotations in primate models of parkinsonism. J Neural Transm 46. Verhagen Metman L, Del Dotto P, Natte´ R, van den Munckhof P, Chase TN. Dextromethorphan improves levodopa-induced 25. Gomez-Mancilla B, Bedard PJ. Effect of nondopaminergic drugs dyskinesias in Parkinson’s disease. Neurology 1998;51:203– on L-DOPA-induced dyskinesias in MPTP-treated monkeys. Clin 47. Verhagen Metman L, Del Dotto P, van den Munckhof P, Fang J, 26. Trabucchi M, Bassi S, Frattola L. Effects of naloxone on the Mouradian MM, Chase TN. Amantadine as treatment for dyski- “on-off” syndrome in patients receiving long-term levodopa ther- nesias and motor ﬂuctuations in Parkinson’s disease. Neurology apy. Arch Neurol 1982;39:120 –121.
27. Sandyk R, Snider SR. Naloxone treatment of L-dopa-induced 48. Strong JA, Dalvi A, Samaha FJ, Gong J, Xu K, Yue X, Yu L. Mu dyskinesias in Parkinson’s disease. Am J Psychiatry 1986;143:118.
opioid receptor polymorphisms and L-Dopa induced dyskinesia inParkinson’s disease. Proc Soc Neurosci 1999;25:846.2.
28. Price P, Baxter RC, Parkes JD, Marsden CD. Opiate antagonists and Parkinson’s disease. Arch Neurol 1979;36:661.
29. Nutt JG, Rosin AJ, Eisler T, Calne DB, Chase TN. Effect of an opiate antagonist on movement disorders. Arch Neurol 1978;35:810 – 811.
30. Rascol O, Fabre N, Blin O, et al. Naltrexone, an opiate antagonists, fails to modify motor symptoms in patients with Parkinson’s disease. Mov Disord 1994;9:437– 440.
31. Manson AJ, Katzenschlager R, Hobart J, Lees AJ. High dose naltrexone for dyskinesias induced by levodopa. J Neurol Neuro-surg Psychiatry 2001;70:554 –556.
Stuart J. Fellows, PhD,* and Johannes Noth, MD 32. Delitala G, Giusti M, Mazzocchi G, Granziera L, Tarditi W, Giordano G. Participation of endogenous opiates in regulation of Neurologische Klinik, Universita¨tsklinikum the hypothalamic-pituitary-testicular axis in normal men. J Clin Endocrinol Metab 1983;57:1277–1281.
33. Bonuccelli U, Piccini P, Del Dotto P, Rossi G, Corsini GU, Muratorio A. Naloxone partly counteracts apomorphine side ef- Abstract: In recent years it has been shown that a variety of
fects. Clin Neuropharmacol 1991;14:442– 449.
movement disorders are associated with abnormalities of
34. Limone P, Calvelli P, Altare F, Ajmone-Catt P, Lima T, Molinatti the ﬁne motor control of the hand. In Parkinson’s disease
GM. Evidence of an interaction between alpha-MSH and opioids (PD), these changes consist of a slowing of the rate of grip
in the regulation of gonadotropin secretion in man. J Endocrinol force development and the use of abnormally large grip
forces both during lifting and static holding of an object. It
35. Coiro V, Volpi R, Capretti L, et al. Different effects of naloxone on has been suggested, however, that these changes are a direct
the growth hormone response to melatonin and pyridostigmine in effect of the patient’s levodopa medication or associated
normal men. Metabolism 1998;47:814 – 816.
with levodopa induced dyskinesias. Accordingly, we exam-
36. Tomasi PA, Fanciulli G, Palermo M, Pala A, Demontis MA, ined the performance of de novo Parkinson patients in a
Delitala G. Opioid receptor blockade blunts growth hormone (GH) precision lifting task. All patients (n ؍ 6) were newly diag-
secretion induced by GH-releasing hormone in the male. HormMetab Res 1998;30:34 –36.
nosed and showed rigidity, bradykinesia, or both, but were
37. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical unaffected by tremor or dyskinesia. None of the patients
diagnosis of idiopathic Parkinson’s disease: a clinico-patholog-ical study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181–184.
*Correspondence to: Dr. Stuart Fellows, Neurologishe Klinik, Uni- 38. Langston JW, Widner H, Goetz CG, Brooks D, Fahn S, Freeman versita¨tsklinikum der RWTH Aachen, Pauwelsstr. 30, D-52074 T, Watts R. Core assessment program for intracerebral transplan- Aachen, Germany. E-mail: firstname.lastname@example.org tations (CAPIT). Mov Disord 1992;7:2–13.
Received 1 August 2003; Revised 25 September 2003; Accepted 13 39. Evans JM, Hogg MI, Lunn JN, Rosen M. Degree and duration of reversal by naloxone of effects of morphine in conscious subjects.
Published online 18 December 2003 in Wiley InterScience (www.
interscience.wiley.com). DOI: 10.1002/mds.10710
Movement Disorders, Vol. 19, No. 5, 2003 GRIP FORCE ABNORMALITIES IN DE NOVO PD had received antiparkinson medication. Grip force was
TABLE 1. Clinical details of the patients
abnormally high in both the lifting and hold phases. This
exaggeration was equal in magnitude to that observed pre-
viously in medicated patients. Thus we conclude that the
abnormalities in grip force observed here are intrinsic fea-
tures of PD and not the result of dopamine medication or its
side effects. 2003 Movement Disorder Society
Key words: Parkinson’s disease; de novo; precision grip
In recent years it has been shown that a variety of Stage 0, no signs of disease; Stage 1, unilateral disease; Stage 1.5, unilateral plus axial involvement; Stage 2, bilateral disease without movement disorders are associated with abnormalities of impairment of balance; Stage 2.5, mild bilateral disease with recovery ﬁne motor control of the hand.1–7 In Parkinson’s disease on pull test; Stage 3, mild to moderate bilateral disease, some postural (PD), these changes consist of a slowing of the rate of instability, physically independent; Stage 4, severe disability, still ablewalk or stand unassisted; Stage 5, wheelchair-bound or bedridden grip force development8 and the use of abnormally large grip forces, during both lifting and static holding of an object.9,10 It has been suggested, however, that thesechanges were a direct effect of the patient’s levodopa(L-dopa) medication.11 This claim is somewhat surpris- Details of the apparatus and methods employed have ing, given the improved quality of movement generally been fully described elsewhere.9 Brieﬂy, the investiga- reported by the patients themselves, and indeed, L-dopa tion was carried out in a quiet room with subdued light- medication has been shown to markedly improve reach- ing. The subject was seated in a stable chair that sup- to-grasp movements in patients with PD.12 A more likely ported the back (but not the head) before a table on which suggestion was that the exaggerated grip force levels was situated the lifting device. Subjects were positioned resulted from L-dopa induced dyskinesias.13 Accord- so that they were able to grip the object between their ingly, we examined the performance of de novo Parkin- foreﬁnger and thumb and lift and hold the object at the son patients in a precision lifting task. These patients wrist while their elbow remained fully supported on a were in the early stages of the disease and did not exhibit padded rest. The measuring instruments built into the tremor or dyskinesia as part of their symptoms. They had device registered the grip force exerted on the object had no exposure to L-dopa or other dopaminergic medi- (9301b; Kistler, Winterhur, Switzerland) and its vertical cation, and so their performance clearly could not be position (T60500; VAC, Mu¨nchen, Germany). These inﬂuenced, directly or indirectly, by effects of signals were ampliﬁed and then passed to the analogue- We show that they demonstrated grip force abnormalities to-digital converter board (NI-PCI-MIO-16XE; National compatible with those of a group of parkinsonian pa- Instruments, Austin, TX) of a laboratory computer (Macintosh PPC 7600/132; Apple, Cupertino, CA) sam- abnormalities are an intrinsic feature of the pathophysi- ology of PD. An alternative explanation for these deﬁcits The subjects were required, without visual feedback concerning hand position, to grip and lift the object 4 to6 cm above the table, then hold it steady for 6 to 8seconds before replacing the object on the table and SUBJECTS AND METHODS
releasing it. The contact pads on the object for thumb and The study involved 6 patients who were referred to our foreﬁnger were covered with sandpaper (extra-ﬁne, corn outpatient clinic with a suspected and subsequently con- 400). A second laboratory computer (Macintosh IIVX; ﬁrmed diagnosis of PD (Table 1). In cases of hemipar- Apple) was used to control the load of the object via a kinsonism, the affected hand was studied, whereas in the servo-device. A torque motor attached via a nonelastic other cases the dominant hand was used. None of the band to the object was used to alter object load between patients was receiving or had received parkinsonian lifts without the subject’s knowledge in a pseudo-random medication. A control group comprised 12 age-matched manner between two levels, namely 3.3 N (light) and 7.8 subjects (6 men, 6 women; mean age, 61 Ϯ 3 years) with N (heavy), such that ﬁve lifts could be selected for each no history of neurological disorder. All subjects gave load where the load remained unaltered from the preced- their informed consent to the procedures, which had been ing lift. A 10- to 15-second pause was allowed between approved previously by the local ethics committee.
Movement Disorders, Vol. 19, No. 5, 2003 status and object load as the main factors. Post-hoctesting was carried out using the Tukey-Kramer test.
All 6 de novo PD patients displayed obvious abnor- malities in their grip force curves. Figure 2 shows 5 gripforce proﬁles obtained while lifting a light load for arepresentative control subject (upper traces) and a patientwith PD (lower traces). It is apparent that the patientdeveloped grip force markedly slower than did the con-trol subject, and consistently employed exaggerated lev-els of grip force, in both the dynamic and static phases ofthe lift.
The group values for the four lifting parameters are displayed in Figure 3. Each dot represents the value of asingle parkinsonian patient, whereas the grey boxes rep-resent the mean value for the control group (ϮSEM).
FIG. 1. The grip force and object position curves for a typical control
The mean values for the patients with PD are shown as subject lifting the light load. The parameters obtained from these curves ﬁlled triangles. Figure 3A shows the data for the IGL. It are numbered. 1, Time between onset of grip force development and
object lift-off (IGL), a measure of ﬁnger/wrist co-ordination; 2, time
may be seen that the parkinsonian patients all demon- taken to achieve peak grip force (TPGF), a measure of the rate for grip strated timings outside or at the upper end of the range of force development; 3, peak grip force (PGF) developed in the dynamic
values shown by the control group. On a group basis, this lifting phase, a measure of pre-planned matching of grip force to object
properties; and 4, static grip force (SGF), the grip force developed
prolongation was highly signiﬁcant (P Ͻ 0.01) and its while holding the object steady above the table, a measure of grip force magnitude was comparable with that observed in an adaptation to actual conditions based on cutaneous afferent feedback.
The grip force curves obtained from each of the lifts carried out was measured subsequently (see Fig. 1) toyield a series of parameters: (1) IGL, the time betweenthe onset of grip force and the lift-off of the object(msec); (2) TPGF, the time taken to reach the peak gripforce (msec); (3) PGF, peak grip force magnitude (N);and (4) SGF, the stable grip force adopted while holdingthe object steady above the table (N). The IGL may beconsidered to provide a measure of the co-ordinationbetween the ﬁngers gripping the object and more prox-imal arm muscles responsible for the actual horizontallift of the object. TPGF provides information about therate of grip force development at the ﬁngers. PGF pro-vides information on the largely automatic processes ofthe selection from memory of motor sets matched toobject properties,14 whereas the SGF is the result ofmodiﬁcation of these stored commands by actual sensoryfeedback concerning object properties obtained duringthe lift itself.15 Statistical analysis was carried out using the Statview 5.0 package (SAS Institute, Cary, NC). For this purpose, FIG. 2. The 5 grip force proﬁles obtained while lifting the light load
the median value obtained from ﬁve lifts with a given by a typical control subject (upper traces) and a patient with PD (4,lower traces). Grip force development clearly was slower in the patient, load were obtained for each parameter and compared who also developed consistently excessive force levels during both the between subjects using MANOVA analysis with clinical dynamic lifting phase and the static hold phase.
Movement Disorders, Vol. 19, No. 5, 2003 GRIP FORCE ABNORMALITIES IN DE NOVO PD FIG. 3. Group values for the four lifting pa-
rameters. Each dot represents the value of a
single parkinsonian patient, whereas grey boxes
represent the mean value for the control group
(ϮSEM). The parkinsonian mean is represented
by a ﬁlled triangle. All four parameters showed
a signiﬁcant increase over control values in PD
(P Ͻ 0.01, except TPGF, P Ͻ 0.05). The adap-
tation of the values according to load seen in the
control group was maintained in PD, with the
exception of TPGF (IGL, P Ͻ 0.05; PGF, SGF,
P Ͻ 0.01). The percentage values under each
load give the increase in the parkinsonian mean
relative to the control mean. Abnormalities are
more evident with the lighter load, and grip
force is exaggerated especially in the static
earlier study9 involving patients at a later stage of the grip force to load was retained (P Ͻ 0.01). It is interest- disease who were on a stable regime of L-dopa medication.
ing to note that the exaggeration was more marked for IGL modulation with load remained signiﬁcant (P Ͻ 0.05) the light load (on average, twice the mean level of the in the parkinsonian patients. The relative increase over control group) than for the heavy load (on average, an control values (ϳ60%) was equal for both loads.
increase of two-thirds). The exaggeration was also more TPGF values for the parkinsonian patients (Fig. 3B) marked than that observed previously in the patients with were also prolonged relative to the control group (P Ͻ a longer duration of disease,9 although the fact that the 0.05). This prolongation was less marked, however, than latter were receiving L-dopa medication must be borne in that observed previously in patients with a longer disease mind. Figure 3D shows the data for SGF and it can be duration.9 The modulation of timing with load observed seen that a signiﬁcant exaggeration of grip force levels in in the latter group of patients and in the control group de novo PD patients occurred (P Ͻ 0.01), even more was not signiﬁcant in the group of de novo patients.
marked than in the dynamic phase of the lift, particularly The most pronounced abnormalities shown by the de for the light load, where the exaggeration over control novo patients were observed in the exaggerated levels of values was (in relative terms) almost twice as great as grip force employed in both the dynamic and static that observed with the heavy load. Scaling of grip force phases of the lift. PGF values (Fig. 3C) for patients were to load was retained (P Ͻ 0.01). Once again, the exag- signiﬁcantly higher than control values (P Ͻ 0.01) for geration was more marked than that observed previously both the light and the heavy load, although the scaling of in patients with a longer duration of disease.9 Movement Disorders, Vol. 19, No. 5, 2003 DISCUSSION
that patients with PD suffer a decreased sensitivity to sen- An unequivocal result of this study is that grip force sory input acting on structures at a cortical level. We would abnormalities were present in the early stages of PD, in argue that this is supported further by our ﬁndings. Firstly, although the scaling of grip force levels to load was main- more, the greatest abnormalities were observed in grip tained, a general shift to larger values was found. Secondly, force magnitude. Thus the hypothesis put forward by the extent of the exaggerated grip force relative to the Gordon and Reilmann,11 that exaggerated grip forces are control values was signiﬁcantly higher for the light load than for the heavy load. As more afferent input would be L-dopa medication, is contradicted by our ﬁndings. Another suggestion, namely that exaggerated expected in the latter case, it could be argued that theexaggerated grip force levels result from a degree of insen- grip force levels result from L-dopa-induced dyskine- sitivity to afferent input caused by an upward shift in the sia,13 can also be ruled out as an explanation for our threshold level at which sensory input can act effectively.
ﬁndings, as none of the patients showed dyskinesia and The ﬁnding that the relative grip force abnormalities are as de novo patients had had clearly no chance to develop most pronounced for the SGF, the control of which relies L-dopa-induced dyskinesia. Indeed, the grip force pro- heavily on cutaneous feedback information, further sup- ﬁles of parkinsonian patients with L-dopa-induced dys- kinesia (Wenzelburger and associates,13 Fig. 2C) resem- In summary, we conclude that exaggerated grip force observed in patients with PD are intrinsic features of the Huntington’s disease (see Hermsdo¨rfer and colleagues,5 pathophysiology of the disease, and not the result of Fig. 2A) than the markedly slowed proﬁles obtained in dopamine medication or its side effects. Rather, we sug- the present study and in a group of PD patients on a gest that abnormalities arise from decreased efﬁciency in stable L-dopa regime,9 indicating that a different patho- the utilization of sensory input concerning object prop- physiology may underlie the two phenomena.
erties and the performance of the motor apparatus.
Although this is more a matter of interpretation, we would also argue that the present results provide strong Acknowledgments: This work was supported by grants
support for the hypothesis that grip force abnormalities in a from the Deutsche Forschungsgemeinschaft as part of the pro- variety of basal ganglia disorders result from a disturbance gram SPP 1001 “sensomotorische Integration”. We thank Pro-fessor M. Schwarz, Dr. R. To¨pper, and Dr. P. Weiss-Blanken- of sensorimotor processing.5,9,16 This idea arose in part horn for fruitful discussions of our ﬁndings.
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ential deﬁcit between verb and noun processing. Clinicalevidence5–9 shows a relationship between object-namingdeﬁcit and damage to the left temporal lobe, and between action-naming deﬁcit and large lesions in the left frontalcortex. Damasio and Tranel7 formulated the hypothesis that in the left hemisphere, noun retrieval is mediatedpreferentially by temporal regions, whereas verb re- Jean-Franc¸ois De´monet, MD, PhD, Cyril Pernet, MSc, trieval is subserved by a large network including the prefrontal cortex; this hypothesis has received further Institut National de la Sante´ et de la Recherche Me´dicale U support in studies devoted to degenerative diseases af- 455, Fe´de´ration de Neurologie, Centre Hospitalier fecting the frontal cortex. A verb deﬁcit was observed in Universitaire Purpan, Toulouse, France frontotemporal dementia10 and in motor neuron diseaseassociated with pathological changes in two frontal ar- Abstract: We compared noun- and verb-generation tasks in
eas, namely Brodmann areas 44 and 45.11 Language a demented group (n ؍ 9, Dementia Rating Scale < 129)
studies in Parkinson’s disease (PD) have also revealedthe existence of such dysfunction; Grossman and col-leagues12 showed a verb learning impairment in a group *Correspondence to: Patrice Pe´ran, INSERM U 455, CHU Purpan, 31059 Toulouse Cedex 3, France. E-mail: email@example.com of early PD patients. Our group has shown recently that Received 26 April 2003; Revised 23 July 2003, 8 October 2003; word generation tasks may be useful to unveil in non- demented PD patients a speciﬁc impairment of verb Published online 12 December 2003 in Wiley InterScience (www.
interscience.wiley.com). DOI: 10.1002/mds.10706
production compared with noun generation.13 Movement Disorders, Vol. 19, No. 5, 2003
Manufacturer:Nanjing Taiye Chemical Co.,ltdCHEMTREC (EMERGENCY ONLY):0086-513-84081230 E Lithium Chloride, solution N : 7447-41-8 Y Alkali Chloride N : Water-white liquid S This product is moderately irritating to the skin, eyes, nose and throat. Ingestion may cause drowsiness, weakness, tremors, anorexia, nausea, blurred vision, and muscle spasm. E Flush with water for at least