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Disclosed is a method for treating a hyperkinetic movement disorder comprising the steps of selecting a first at least one pharmacologically active agent that acts as a GABA-receptor agonist and a second at least one pharmacologically active agent that acts as a NMDA-type glutamate receptor antagonist, and administering the first and second agents at effective and non-toxic dosages.
1. A method of treating hyperkinesia comprising:
administering an effective and non-toxic dose of an agent which is a GABA-receptor agonist and which decreases the response of NMDA-type glutamate receptors.
2. The method of of claim 1 wherein said agent is selected from the group consisting of acamprosate, calcium N-acetylhomotaurinate, salts of N-acetylhomotaurinate, acetylhomotaurinate base, homotaurine and derivatives thereof.
3. The method of claim 2 whereby said method of treating hyperkinesia also improves cognition or memory in humans exhibiting signs of tardive dyskinesia when said response is determined using a standard neuropsychological test.
4. The method of claim 3 wherein said standard neuropsychological test is selected from the group consisting of established clinical tests, established bedside tests of cognition or memory, and observation of a history of performance of everyday activities that are highly dependant on cognitive processes.
5. The method of claim 1 wherein said step of administering comprising oral administration.
6. A method of treating a hyperkinetic movement disorder comprising the steps of:
selecting a first at least one pharmacologically active agent that acts as a GABA-receptor agonist and a second at least one pharmacologically active agent that acts as a NMDA-type glutamate receptor antagonist; and
administering said first and said second agents at effective and non-toxic dosages.
7. The methods of claim 6 whereby said first agent and said second agent are the same agent.
8. The method of claim 6 whereby said movement disorder is tardive dyskinesia or comprises involuntary movements similar to those seen in said tardive dyskinesia.
9. The method of claim 6 whereby said movement disorder is the peak-dose dyskinesia associated with Parkinson's disease or comprises involuntary movements similar to those seen in said peak-dose dyskinesia.
10. The method of claim 6 whereby said movement disorder is associated with Huntington's disease.
11. The method of claim 6 whereby said method further improves cognitive response in humans exhibiting said movement disorder when said response is measured using standard neuropsychological tests.
12. The method of claim 11 wherein said standard neuropsychological test comprises established clinical tests, established bedside tests of cognition and memory, and observation of a history of clear-cut changes in performance of everyday activities highly dependant on cognitive processes.
13. The method of claim 6 wherein said movement disorder is related to a deficiency in GABA in the basal ganglia.
14. The method of claim 6 wherein said movement disorder is related to NMDA-based excitotoxicity.
15. The method of claim 6 comprising the further steps of
selecting a third pharmacologically active agent that is a noncompetitive antagonist at NMDA receptors; and
administering said third agent in conjunction with said first and said second agents.
16. The method of claim 15 wherein said third agent is memantine or a derivative thereof.
Tardive dyskinesia (TD) is a chronic disorder of the nervous system, characterized by involuntary, irregularly rhythmic movements of the mouth, tongue, and facial muscles. The upper extremities also may be involved. These movements may be accompanied, to a variable extent, by other involuntary movements and movement disorders. These include rocking, writhing, or twisting movements of the trunk (tardive dystonia), forcible eye closure (blepharospasm), an irresistible impulse to move continually (tardive akathisia), jerking movements of the neck, and disrupted respiratory movements (respiratory dyskinesia). The vast majority of cases of TD are caused by the prolonged use of antipsychotic drugs (neuroleptics). (A relatively small number are caused by the use of other medications, such as metoclopramide, that block dopamine receptors.) TD can manifest, or worsen in severity, after neuroleptic drug therapy is discontinued.
The cumulative incidence of TD in patients exhibiting a first episode of schizophrenia who have undergone a four-year course of neuroleptic treatment is 16.5% (Chakos et al., Arch. Gen. Psychiatry 53:313,1996). The cumulative incidence is substantially higher in older people and in those being treated with neuroleptics for conditions other than schizophrenia, such as bipolar disorder (manic-depressive illness) (see, e.g., Hayashi et al., Clin Neuropharmacol 19:390, 1996, Jeste et al., Arch. Gen. Psychiatry 52:756, 1995).
TD is associated with a variable degree of cognitive impairment. Cognitive dysfunction associated with TD may involve attention, concentration, memory, or executive functions such as judgment or abstract reasoning. (see, e.g., Sachdev et al., Acta Psychiatr Scand 93:451, 1996; Waddington & Youssef, Psychol Med. 26:681, 1996; Swartz, Neuropsychobiology 32:115, 1995).
While the pathophysiologic mechanism of tardive dyskinesia is unknown, it has been established that chronic or prolonged administration of typical neuroleptics, all of which act by blocking dopamine receptors results in hypersensitivity or up-regulation of dopamine receptors in the basal ganglia. (see e.g., Andrews, Can J Psych 39:576, 1994; Casey, D. E. in Psychopharmacology: The Fourth Generation of Progress, Raven Press, 1995). The first major hypothesis about the pathophysiology of TD was that TD was the result of this neuronal hypersensitivity to the effects of dopamine. Drugs that increase or enhance dopamine response, especially indirect dopamine agonists, can aggravate the disorder. Many psychiatrists avoid using dopamine agonist anti-Parkinson drugs in neuroleptic therapy because of a concern that increased dopamine will aggravate tardive dyskinesia. (Bezchibnyk-Butler & Remington, Can J. Psych. 39:74, 1994).
Other studies have suggested that irreversible cases of tardive movement disorders may be related to excitotoxic damage to the basal ganglia (Andreasen & Jorgensen, 1994). An acquired deficiency of the inhibitory neurotransmitter GABA has also been implicated in the development of TD (Delfs et al. Experimental Neurol. 133:175-188, 1995).
The physical manifestations of TD can resemble movement disorders associated with degenerative diseases such as Huntington's disease and Parkinson's disease. In particular, patients with Huntington's disease may demonstrate limb movements (chorea) similar to those seen in patients with TD. In addition, the neck, trunk and limb movements of TD may resemble those caused by the "peak-dose dyskinesia" associated with prolonged levodopa treatment of Parkinson's disease.
Recent research suggests that Vitamin E can reduce symptoms of TD modestly (Lohr & Caliguiri, J Clin Psychiatry 57;167, 1996; Dabiri et al. 1994). GABA agonists such as baclofen and various benzodiazepines have also been the subject of some positive reports and are widely used in practice to ameliorate the symptoms of TD. (Gardos & Cole, "The Treatment of Tardive Dyskinesias", in Psychopharmacology: The Fourth Generation of Progress, eds. Bloom and Kupfer, pp. 1503-1510, 1995). This same review reports variable benefits associated with other agents including propranolol, clonidine, cholinergic agonists, buspirone and calcium-channel antagonists. However, none of these has become a generally accepted treatment for either the movement or cognitive disorders associated with TD. In co-pending, commonly-owned application Ser. No. 08/861,801, incorporated herein by reference, treatment with memantine, a congener of amantadine and a N-methyl-D-aspartate type (NMDA) receptor blocker as well as a dopamine agonist, has been suggested as an effective treatment of both the movement and cognitive disorders associated with TD.
Acamprosate (calcium N-acetylhomotaurinate) is the calcium salt of a derivative of the amino acid taurine. It is known to be an agonist at GABA receptors. Moreover, it reduces the postsynaptic response of NMDA-type glutamate receptors and reduces calcium influxes through voltage-operated channels. (Wilde & Wagstaff, Drugs 53:1039-53, 1997) Acamprosate is used clinically in the treatment of abstinent alcoholics to reduce or inhibit the craving for alcohol. Animal studies, reported in U.S. Pat. No. 4,355,043 issued to Durlach, showed that acamprosate had an anticonvulsant effect in one specific animal model.
An object of this invention is to develop methods for treating tardive dyskinesia using acamprosate or other homotaurine derivatives.
Another object of this invention to develop methods to treat other hyperkinetic movement disorders (i.e. tardive movement disorders) associated with prolonged exposure to neuroleptic medications or other dopamine receptor blocking agents, using acamprosate or other homotaurine derivatives with similar pharmacologic actions.
Another object of this invention is to develop methods for treating cognitive disorders, including impairments in memory associated with tardive dyskinesia and other movement disorders that are associated with prolonged exposure to neuroleptic medications.
Another object of this invention is to develop methods to treat the peak-dose dyskinesia associated with Parkinson's disease.
More particularly, it is an object of the invention to reduce the severity and duration of involuntary movements associated with tardive dyskinesia.
More particularly, it is the object of this invention to develop methods for improving cognitive function in patients exhibiting TD, specifically to increase memory, span of concentration, and everyday functional performance in activities particularly dependant upon cognition. These improvements in function are measured both subjectively and objectively. The improvement in memory can be demonstrated by standard neuropsychological tests.
Another object of the invention is to develop methods of treating or retarding the onset of tardive dyskinesia in abstinent alcohol abusers who are treated with neuroleptics for concurrent mental disorders, such as bipolar disorder and schizophrenia.
The invention relates to a method of treating tardive dyskinesia and similar movement disorders in humans. In one aspect, the invention reduces involuntary movements or hyperkinesia characteristic of patients with tardive movement disorders, including tardive dyskinesia, by the administration of a pharmacological agent such as acamprosate or other homotaurine derivative that acts as an agonist at GABA receptors and also decreases NMDA receptor function by an indirect or modulatory mechanism.
A final object of this invention is to develop a method of treating TD and related conditions by combining memantine or a similar non-competitive NMDA receptor antagonist with acamprosate or another compound or mixture that simultaneously decreases the postsynaptic response to glutamate at NMDA-type receptors and also acts a GABA agonist.
In relation to the first aspect of the invention, I have discovered that an agent used in the treatment of abstinent alcoholics, not contemplated for use in treatment of tardive dyskinesia, are effective in reducing the hyperkinesia of patients with TD. Several years ago, I hypothesized that TD represents a form of non-linear oscillation in neural circuits involving the basal ganglia, and that oscillation might be reduced by agents that block excitatory neurotransmission. Evidence from PET scans documented increased metabolism in the globus pallidus and primary motor cortex in schizophrenic patients with TD, but not in those without TD (Pahl et al., J Neuropsych Clin Neurosci 7:457, 1995). This suggests that TD is associated with hyperactivity in a motor control circuit, which might be part of the putative nonlinear oscillator.
As noted above, I have advanced the hypothesis that agents which act to reduce the gain in a motor control circuit through the striatum, may have a beneficial action on TD and related movement disorders. GABA is an inhibitory neurotransmitter in the striatum. Thus, support for my hypothesis comes from animal evidence that agents that directly or indirectly stimulate GABA receptors can decrease neuroleptic-induced dyskinesias (Stoessl, Pharmacol Biochem Behav 54:541, 1996; Gao et al. J Neural Transmission 95:63, 1993). Rats with neuroleptic-induced dyskinesia demonstrate decreased striatal levels of glutamic acid decarboxylase, the rate-limiting enzyme in the production of GABA (Delfs et al., Exp Neurol 133:175, 1995).
Without limiting the biochemical mechanism of the invention to that described here, it appears that drugs that act to reduce the gain in the hypothesized oscillator circuit would reduce the involuntary movements of tardive dyskinesia. In my co-pending patent application, Ser. No. 08/861,801, the teachings of which are incorporated herein by reference, I disclosed that certain antagonists of excitatory neurotransmitters were effective in treating both the movement and cognitive disorders associated with TD and other hyperkinetic movement disorders. In the current invention, I disclose that acamprosate, a GABA-receptor agonist that also diminishes the postsynaptic response of NMDA-type receptors to glutamate can ameliorate TD as well as related involuntary movements and cognitive symptoms. From this, and from hypothesis advanced earlier, I infer that a broad range of agents with similar concurrent action on GABA and NMDA receptors will diminish the symptoms and signs of TD and related disorders. These include derivatives of homotaurine and N-acetylhomotaurine.
In one preferred embodiment of this aspect of the invention, a pharmaceutical agent is selected from the group of agents that act as GABA-receptor agonists and also act to decrease NMDA receptor function by an indirect or modulatory mechanism such as, in a non-limiting fashion, acamprosate calcium (calcium N-acetylhomotaurinate), other salts of N-acetylhomotaurinate, acetylhomotaurine base, homotaurine or derivatives of these compounds ("Drug List A"). In another preferred embodiment, a pharmaceutical agent is selected from the group of agents that have the ability to reduce excitatory post-synaptic potentials in striatal cells induced by glutamate, such as, in a non-limiting fashion, acamprosate calcium, calcium acetyl homotaurinate, homotaurine or derivatives of these compounds. In another preferred embodiment, a combination of two or more pharmaceutical agents is selected such that the combination acts concurrently to stimulate GABA-receptors and to attenuate the response of NMDA-type glutamate receptors. A third embodiment is to combine such a compound or mixture with memantine or a similar non-competitive NMDA-receptor blocking agent.
A second aspect of the invention features a method of improving cognitive memory and cognition in humans with TD, where the latter is demonstrated by performance on neuropsychological tests, including without limitation, the Rey Auditory-Verbal Learning Test, and measurement of Choice Reaction Time, and by subjective indicators of performance at tasks highly dependent on cognitive processes. It will be obvious to one skilled in the art that numerous different neuropsychological tests could be employed to demonstrate that cognitive function improved in patients on a treatment regime that included acamprosate.
GABA-receptor agonists can be used according to the method of the invention to reduce the severity of hyperkinesia associated with tardive dyskinesia. However, such agents have not been shown to mitigate the severity of the cognitive dysfunction associated with TD.
Generally, the method of the invention can be used for the treatment of tardive dyskinesia, including the treatment of the hyperkinesia, cognitive disorders and excitotoxic-related neurological damage associated with the disorder.
The method relates to the administration of an effective dose of a GABA-receptor agonist chosen from among a group of GABA-receptor agonists that also modulate NMDA-type glutamate receptors so as to decrease their response, which include, in a non-limiting fashion, acamprosate calcium (calcium N-acetylhomotaurinate) other salts of N-acetylhomotaurinate, acetylhomotaurinate base, homotaurine or derivatives of these compounds.
Acamprosate is a GABA-receptor agonist that resembles the inhibitory neurotransmitter GABA. Acamprosate also reduces the post-synaptic response of NMDA-type glutamate receptors and reduces calcium influxes through voltage-operated channels.
In the method of the claimed invention, "acamprosate" refers to acamprosate calcium (calcium N-acetylhomotaurinate) other salts of N-acetylhomotaurinate, acetylhomotaurinate base, homotaurine or derivatives of these compounds.
In the method of the claimed invention, "GABA-receptor agonist" refers to molecules that are capable of binding to active or modulatory sites on the GABA receptor.
In the method of the claimed invention, "effective" dose refers to one that is administered in doses tailored to each individual patient manifesting symptoms of tardive dyskinesia sufficient to cause a reduction in the associated hyperkinesia or an improvement in the associated cognitive disorders with tolerable adverse effects. Experimentally, doses of acamprosate ranging from 333 mg. to 666 mg. administered three to four times daily have been shown to be effective, but a person skilled in the art will recognize that treatment of patients with pharmaceutical agents must be tailored to the individual patient, taking into account the patient's height, weight, rate of absorption and metabolism of the medication in question, and stage of the disorder to be treated, as well as what other pharmacological agents are administered concurrently, if any.
The following case reports illustrate the preferred method of the invention:
A 45-year old woman had long-standing TD, originally induced by seven years exposure to amoxapine, an antidepressant drug with neuroleptic effects. The patient's irregularly-rhythmic movements consisted of forced eye blinking (blepharospasm), thrusting of the tongue forward and from side to side, tongue twisting, grimacing, shoulder shrugging, and tensing of the platysma muscles of the neck. The patient is a semi-professional musician; the dyskinetic movements were accompanied by significant occupational disability, including difficulty reading music or text and difficulty playing woodwind instruments. She had impaired attention, concentration and memory compared with her performance before onset of TD. She had significant fatigue, and usually required rest at some point during each day. The patient was diagnosed with TD by a board-certified neurologist with extensive experience in evaluating neuroleptic-induced side effects.
Hyperkinesia worsened after the amoxapine was discontinued. Palliative treatment with alprazolam (an anxiolytic and GABA agonist via modulation; dosage 0.25 mg four times a day) and trihexyphenidyl (an anticholinergic antiparkinson drug that inhibits dopamine re-uptake at synapses; dosage 2 mg twice a day) was prescribed by another physician. This combination produce minimal improvement. The patient began treatment with me in the winter of 1992 and was maintained on trihexyphenidyl for an additional 18 months. Trihexyphenidyl was then discontinued without a change in her involuntary movements. During 1993, alprazolam was increased to 0.5 mg four times a day, to treat mild symptoms of anxiety; the change in dosage had no detectable effect on the patient's involuntary movements.
Treatment trials with buspirone, sertraline, verapamil, and vitamin E in 1992 either produced little benefit or were not tolerated at doses that slightly reduced her involuntary movements. None of these drugs significantly improved the patient's everyday function, i.e., her performance at reading text or music, her stamina or her ability to concentrate. The first drug that provided significant and sustained benefits was nimodipine, a cerebroselective calcium channel blocker, which, beginning in 1993, was administered in a regime that included 30 mg of nimodipine four times a day. This regime reduced the patient's hyperkinesia by about 50% but she experienced adverse effects, including dizziness, lightheadedness, and palpitations and had no symptomatic improvement in cognitive function. There was a meaningful improvement in her ability to read and to play music. However, even with this improvement, she could read text or music for no more than 30 minutes at a time, before fatigue or blepharospasm prevented her continuing.
In 1995, memantine came to my attention as a relatively non-toxic NMDA receptor antagonist. In view of my hypothesis about the pathophysiology of tardive dyskinesia, I thought that memantine might be beneficial in its treatment. Nimodipine was discontinued, and the patient was begun on memantine at a dosage of 10 mg twice a day. The hyperkinetic movements with TD were reduced within 24 hours of administration of memantine, to a substantially greater degree than had been observed with nimodipine. Adverse effects included a sense of mild intoxication. Adjustments to the therapeutic regime were made such that the drug was reduced to 5 mg three times a day, with the result that the therapeutic benefits were maintained without perceptible side effects. In addition, the patient reported improved energy, attention, and concentration.
Prior to treatment with acamprosate, the patient's involuntary movements (on an optimal dose of memantine) consisted of eye blinking, puckering of the cheeks, writhing of the tongue and tensing of the platysma. These involuntary movements were usually mild and occasionally moderate in intensity. The movements had been substantially more severe in the past, but had been reduced significantly during the course of two-year course of treatment with memantine, an NMDA-type glutamate receptor antagonist. Moreover, the patient's involuntary movements were accompanied by mild but definite cognitive impairment. The patient's most prominent cognitive symptom was difficulty sustaining concentration long enough to read more than a few pages of text.
The patient was taken off of memantine and treated with acamprosate, using a treatment regime of 333 mg. acamprosate given four times a day. On acamprosate, the patient's involuntary movements became imperceptible.
In addition, the patient's cognitive function improved significantly when measured both subjectively and objectively. For example, the patient was able to sustain concentration for prolonged periods while on acamprosate, including the ability to read a book for over an hour at a time, with good recall of what she had read. The patient's cognitive improvement was also assessed using formal neuropsychological measures. The patient was tested while on the drug, then taken off of the drug and tested two days later. On the drug, the patient was able to recall 13 of the 15 items after a short delay as well as 13 of the 15 items after a long delay, as measured by the Rey Auditory Verbal Learning Test. This was in comparison to the patient's ability while off the drug to recall only 7 of the 15 items after a short delay as well as 8 of the items after a long delay in tests performed. In addition, the patient was able to recognize all 15 of the items while on acamprosate but while off the drug (and while having been off of memantine for over 2 months) the patient could only recognize 10 of the items.
Comparison with other neuropsychological tests demonstrated that the improved cognitive findings shown while the patient was on acamprosate were not explained by a nonspecific lack of effort or to concentration during the period that the patient was not on the acamprosate regime. These additional tests, which reflect basic attention and psychomotor speed, showed that the patient had slightly better results off acamprosate for attention and concentration. The tests showing such results included Simple Reaction Time, the Trail Making Test (both parts) and the Paced Auditory Serial Addition Test (PASAT). Choice reaction time, a test requiring both basic attention and concentration on a specific task that must be kept in mind, was slightly better on acamprosate, consistent with the hypothesis that general cognitive function, as opposed to simple attention, improves with acamprosate treatment. In addition, normal results were shown while on and while off acamprosate during a vigilance test.
The following tables report on the results of these neuropharmalogical tests (Drug I is memantine and Drug II is acamprosate):
TABLE 1__________________________________________________________________________REACTION TIME, PSYCHOMOTOR SPEED, & MOTOR FUNCTIONINGFOR DRUG I (MEMANTINE) AND DRUG II (ACAMPROSATE) 2/23/96 ON 4/8/96 OFF 9/23/97 ON 9/25/97 OFFTESTS 2/23/94 DRUG I DRUG I DRUG II DRUG II__________________________________________________________________________Simple ReactionTimea1500 Green NA 212 msec 332 msec 261 msec 234 msec1500 Red NA 224 msec 276 msec 264 msec 241 msec500 Green NA 284 msec 343 msec 286 msec 272 msec500 Red NA 266 msec 382 msec 272 msec 237 msecChoice ReactionTimea1500 Green NA 365 msec 542 msec 408 msec 442 msec1500 Red NA 422 msec 643 msec 379 msec 435 msec500 Green NA 362 msec 603 msec 382 msec 425 msec500 Red NA 421 msec 557 msec 426 msec 413 msecPASATa2.4 sec ISI 17/49 13/49 15/49 4/49 0/49errors2.0 sec ISI 17/49 17/49 21/49 1/49 1/49errors1.6 sec ISI 11/49 21/49 22/49 11/49 4/49errors1.2 sec ISI 17/49 28/49 25/49 13/49 11/49errorsDigit Symbolb NA 34 20 NA NATrails ASecondsa 25" 28" NA 20" 16"Errorsa 1 0 NA 0 0Motor FunctionsGrooved DH = 68" DH = 71" NA DH = 61" DH = 59"Functions NDH = 82" NDH = 70" NDH = 70" NDH = 76"sec.aDH = rightFinger Tappingb DH = 58.8 DH = 59.3 NA NA NA NDH = 41.6 NDH = 48.5Grip Strengthb NA DH = 17.7 NA NA NA NDH = 21.7__________________________________________________________________________ Note: a lower score indicative of better performance b higher score indicative of better performance
TABLE 2______________________________________EXECUTIVE, ATTENTION, VISUOCONSTRUCTIONAL &VISUAL MEMORY TASKS FOR DRUG I (MEMANTINE) ANDDRUG II (ACAMPROSATE) 2/23/96 4/8/96 9/23/97 9/25/97 ON OFF ON OFFTESTS 2/23/94 DRUG I DRUG I DRUG II DRUG II______________________________________1. Trails BSecondsa 56" 118" NA 43" 39"Errorsab 0 0 NA 0 0VerbalFluencyLetter (CFL)b NA Total = 70 NA NA NA Per = 2bCategory NA Total = 25 NA NA NA(Animals)b Per = 0bFiguralFluencyUnique NA 124 99 NA NADesignsbPerservationsa NA 8 4 NA NA2. CPT - withconditions(Vigilance)Commission 0 NA NA 0 0errorsaOmission 0 NA NA 0 0errorsawronga 3 NA NA 3 0Correctb 50/50 NA NA 100/100 100/1003. Rey-OsterriethComplexFigureCopy Presence NA 20 17 NA NA& AccuracybCopy NA 5 4 NA NAOrganizationbImmediate NA -55 -47.1 NA NARetentionbDelayed NA -11.1 22.2 NA NARetentionb______________________________________ Note: a lower score indicative of better performance b higher score indicative of better performance
TABLE 3______________________________________MEMORY TESTING FOR DRUG I (MEMANTINE) AND DRUGII (ACAMPROSATE) 2/23/96 4/8/96 9/23/97 9/25/97 ON OFF ON OFFTESTS 2/23/94 DRUG I DRUG I DRUG II DRUG II______________________________________CaliforniaVerbalLearningTest 16- itemsList A 1-5 total NA 53 40 NA NA(80 max)bList A Trial 1b NA 7 6 NA NAList A Trial 5b NA 13 9 NA NAList Bb NA 7 5 NA NAShort-Delay NA 10 4 NA NAFree RecallbShort-Delay NA 13 9 NA NACued RecallbLong-Delay NA 12 7 NA NAFree RecallbLong-Delay NA 15 8 NA NACued RecallbPerseverationsa NA 23 4 NA NAIntrusionsa NA 6 0 NA NARecognition NA 16 14 NA NAHitsbFalse Positivesa NA 3 0 NA NARey-AuditoryVerbalLearningTest 15-itemsList A 1-5 toal NA NA NA 63 57(75 max)bList A Trial 1b NA NA NA 10 9Ljst A Trial 5b NA NA NA 14 14List Bb NA NA NA 8 9Short-Delay NA NA NA 13 7Free RecallbLong-Delay NA NA NA 13 8Free RecallbPerseverationsa NA NA NA 5 0Intrusions a NA NA NA 0 3Recognition NA NA NA 15 10HitsbFalse Positivea NA NA NA 1 2______________________________________ Note: a lower score indicative of better performance b higher score indicative of better performance
In addition to a markedly reduced degree of involuntary movements and meaningfully increased cognitive ability experienced by the patient while on the acamprosate regime, the patent also experienced an increase in stamina. Prior to beginning the acamprosate regime, the patient was fatigued by the end of the afternoon, requiring rest in order to be alert in the evening. This fatigue was significantly less while on the acamprosate regime, with a corresponding decline in fatigue-related cognitive function. On acamprosate, the patient no longer needed to rest during the day in order to be alert and active during the evening.
To verify that the acamprosate was related to the patient's improvement in controlling movement disorders, cognitive function and stamina, the patient was removed from the acamprosate regime (as well as the memantine regime) for a period of four weeks. During the initial two-week period off acamprosate, the patient's involuntary movements gradually returned to her pre-acamprosate, off-memantine baseline. (While the patient's off-drug baseline was less severe than it was when she started on memantine two years earlier, her movements still were severe enough to interfere significantly with her everyday functioning.) From that point on, until acamprosate was re-instituted, she showed continual mild-to-moderate grimacing, tensing of the platysma, and forced eye closure. These involuntary movements worsened still further during periods of stress or fatigue. Moreover, the patient fatigued much more easily, to a degree that noticeably reduced her everyday functioning. Subjectively, the patient reported that concentration and memory both decreased.
Within two days of re-instituting treatment with acamprosate, the patient reported that her energy, stamina, concentration and memory improved to the level experienced during her prior treatment with acamprosate. In addition, the patient's involuntary movements were absent except for very mild movements during times of stress.
A 79-year old woman had long-standing TD following decades of treatment with the neuroleptic drug perphenazine. Her involuntary movements comprised bilateral chorea of the upper extremities, plus writhing of the tongue and tongue-biting. Both of the latter movements led to a very sore tongue. In addition, the patient experienced impairment of her short-term memory, which was attributed primarily to cerebrovascular disease.
Following treatment with memantine the patient's voluntary movements improved, but continued at a mild-to-moderate level. She also continued to have a sore tongue. Her cognitive symptoms did not improve. In addition to memantine, the patient regularly took antiepileptic drugs (gabapentin and lamotrigine), antiplatlet agents (aspirin and ticlopidine) as well as medications for hypertension, glaucoma and gastrointestinal symptoms (isosorbide mononitrate, metoprolol, timolol eye drops and olsalazine). These various drugs did not affect the patient's involuntary movements or cognitive symptoms; there was no noticeable change in either one at the time that each of the above-mentioned drugs was instituted.
The patient was placed on a treatment regime that included administration of 666 mg. of acamprosate, three times daily. In this case, acamprosate was added to the patient's regimen, which continued to include memantine. Once the patient began taking acamprosate, her chorea and tongue-biting stopped completely, and the writhing movements of the tongue diminished substantially. Subjectively, the patient's memory improved to the extent that her long-term bridge partner stated that that patient was noticeably better at remembering cards during the play of duplicate bridge. Despite past evidence from formal testing that the patient had impaired short-term memory, she performed normally on a two-sentence memory task, which involved testing the patient's recall ability using two sentences containing 13 separate details. Under the two-sentence memory task, within three attempts the patient was able to recall 9 details and, using a multiple choice format, was able to recall a total of 11 details.
A 56-year old female professor of nursing had had Parkinson's disease since her late 30s. The patient's Parkinson's disease was treated using levodopa/carbidopa and bromocriptine. The patient's profession required a high level of mobility and physical effort, but taking a sufficient dosage of the levodopa/carbidopa to allow adequate physical functioning at work resulted in the patient demonstrating severe peak-dose dyskinesia. The patient's manifestations of peak-dose dyskinesia consisted of writhing movements of the upper trunk, jerky lateral and rotatory movements of the neck as well as chorea of both upper extremities. The patient accepted these involuntary movements because lower dosages of levodopa-carbidopa left her too rigid and hypokinetic to perform her job.
Prior to beginning treatment with acamprosate, the patient was on an antiparkinson treatment regime that consisted of 1 mg. of pergolide administered three times a day, 5 mg. of selegiline administered twice a day, and a combination of levodopa/carbidopa consisting of 550-600 mg. of levodopa and 125-150 mg. of carbidopa administered in divided doses. Additional medications that did not appear to affect her parkinsonism or dyskinesia consisted of bethanecol, sertraline, conjugated estrogens and medroxyprogesterone. (As with the additional medications mentioned in Case 2, there had been no noticeable change in the patient's parkinsonism or dyskinesia after the introduction of each of the drugs listed.) The patient also received 10 mg. of memantine three times a day, which had previously reduced her dyskinetic movements from severe to mild-to-moderate.
The patient began acamprosate as an addition to the antiparkinson regime described above. Initially, the patient received 666 mg. of acamprosate administered three time a day. Two weeks later the regime was adjusted such that the patient received 333 mg. of acamprosate administered four times a day, taking one 333 mg. pill with each dose of 100 mg. levodopa and 25 mg. carbidopa. The patient's bedtime does of controlled-release levodopa-carbidopa (200 mg. of levodopa and 50 mg. of carbidopa) was continued, but given without acamprosate. As soon as acamprosate was added to her regimen, the patient's severe peak-dose dyskinesia was reduced to from moderate to mild intensity, and there were periods of up to two hours following each dose during which there was no dyskinesia at all. There was no decrease in the efficacy of the levodopa/carbidopa treatment of her hypokinesia and rigidity. On acamprosate, the patient experienced longer periods where she was able to exhibit good motor function, and she now had no periods at all where her motor function was inadequate for work or social activity. The reduction of the dyskinesia to a minimal level led to a substantial improvement in purposeful motor function of the upper extremities. Thus, the patient's overall motor function was significantly improved, compared with the treatment regime that did not include acamprosate.
To confirm that the patient's improvement was due to the administration of acamprosate, the patient was taken off the acamprosate, which was replaced first with a daily dose of 30 baclofen (a GABA-receptor agonist) at a total daily dose of 30 mg, and then with baclofen at a total daily dose of 60 mg. These doses of baclofen were high enough to produce sedation and nausea, but they had no beneficial effect on the patient's dyskinesia. Within one day of stopping acamprosate, the patient's dyskinetic movements were as severe as they had been before acamprosate was first given. . . . Upon reinstituting acamprosate, the patient experienced an immediate reduction in her dyskinetic movements. Additional improvement was obtained by replacing the pergolide with 1 mg. of pramipexole administered three or four times a day.
The three patients discussed above all exhibited a marked decrease in the incidence and severity of dyskinetic movements. Those patients who previously exhibited cognitive disorders showed functionally significant improvement in cognitive function after beginning treatment with acamprosate. This evidence supports my novel hypothesis that acamprosate, or a derivative with similar pharmacodynamic actions, will be helpful in the treatment of hyperkinetic movement disorders and associated cognitive disorders. Acamprosate and similar drugs have an action on GABA receptors and effect on the function of NMDA-type glutamate receptors that may be synergistic in regards to the therapy of hyperkinetic movement disorders. To the extent that other related compounds and mixtures of compounds also simultaneously affect GABA and NMDA-type glutamate systems, these related compounds may have the same or similar action on movement disorders or their associated cognitive impairments. Related compounds include, but are not limited to acamprosate calcium (calcium N-acetylhomotaurinate) other salts of N-acetylhomotaurinate, acetylhomotaurinate base, homotaurine or derivatives of these compounds. Derivitives of acamprosate also specifically include those produced by substituting alkyl (e.g. methyl) or aromatic (e.g. benzyl) groups for either or both of the hydrogens in N-acetylhomotaurine. Either those compounds or their salts are included.
Acamprosate may have benefits for treating hyperkinetic movement disorders other that TD. Case 3 suggests that acamprosate was effective in treating a patient with the peak-dose dyskinesia of treated Parkinson's disease. It will be obvious to someone skilled in the art that acamprosate may also benefit patients with hyperkinetic movement disorders with symptoms and/or pathophysiology similar to that of TD or of peak-dose dyskinesia. The movement disorder associated with Huntington's disease is an example. Patients with Huntington's disease may show dyskinetic movements of the face and limbs resembling those of TD. Patients with Huntington's disease have a deficiency of GAD in the striatum, and are thought to suffer from neuronal death due to NMDA-receptor mediated excitotoxicity (D E Riley and A E Lang: Movement Disorders, in W G Bradley et al., editors, Neurology in Clinical Practice, Boston: Butterworth-Heinemann, 1991, p. 1568). These features of the disorder favor a positive response to acamprosate, a drug with joint actions on GAD and NMDA-receptors.
One aspect of the method of the invention features improvements in the cognitive disorder associated with TD. The improvement in cognition and everyday functional performance seen during the treatment of TD, makes acamprosate particularly attractive for patients with cognitive impairment that frequently accompanies TD.
The relationship between tardive dyskinesia and cognitive impairment is not fully understood. It is known that pre-existing cognitive impairment increases the risk that TD will develop in the event a patient receives neuroleptics over a long-term period. It is also known that treated schizophrenics with TD are more likely to show progressive cognitive deterioration that those without TD. However, it is not known whether treatment of TD will ameliorate the cognitive deficits associated with TD. Cases 1 and 2 discussed above suggest that indeed treatment of TD will ameliorate such cognitive deficits given that the prior art does not report that the administration of acamprosate when used as a treatment for alcoholism improves cognitive deficits. Because the prior art does not report that the administration of acamprosate when used as a treatment for alcoholism improved the patients' cognition, it is reasonable to infer that the improvement in cognition seen in Cases 1 and 2 was related to the improvement in their movement disorders. This is consistent with the well-established involvement of the basal ganglia in cognitive processes (Sano et al., Basal Ganglia Diseases)
Moreover, the fact that acamprosate is also known as an agent used in the treatment of alcoholism makes acamprosate particularly suited for the treatment of patients who have a history of alcoholism in addition to a hyperkinetic movement disorder.
Additional tests of the effectiveness of acamprosate are planned, contingent on obtaining an IND permit from the US FDA. Dr. Dilip Jeste of the University of California at San Diego, a world authority on TD, has designed a protocol for an open-label study of 20 patients with severe to extremely-severe TD. The study calls for such patients to be studied over a 12-week period, with objective measures of both involuntary movements and cognition.
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Words Can Be Bullies
Words that start with the letter h don't always act like it.
Consider "herb," when it means "an aromatic plant used for seasoning in cooking." Americans dump the h, whereas many Brits pronounce it. So we say "an 'erb," but an Englishman says "a herb."
A different sort of h-confusion happens when self-important speakers and writers say "an historic occasion" or "an heroic soldier." Ever notice that "an" only precedes a few highfalutin h-words like "historic(al)," "hypothetical," "hallucinogenic"? And they tend to have three or more syllables: "An heroic soldier" is also "a hero."
About 20 years ago, Time magazine ran a front-cover headline beginning, "A Historic…" and misguided word nerds raised a furor, insisting Time should have said "An Historic"—but the magazine never budged, stating flatly that "an historic" is wrong.
In everyday conversation, would you describe a wailing brat as "an hysterical child"? I sincerely doubt it. But what makes "hysterical" so different from "historical"?
A Google check yields tips from various websites, which only reinforce common sense: "You should use 'an' before a word beginning with an 'H' only if the 'H' is not pronounced" (from the website wsu.edu/~brians/errors/anhistoric.html).
Or this: "you use an before vowel sounds…Following this rule, we would say 'a historic,' not 'an historic' " (betterwritingskills.com).
Or this one, which ought to seal the deal: "I'd love to hear a reasonable argument, based on logic and not convention, in support of 'an historic'…given the prevalence of such similar constructions as 'a hotel downtown' and 'a high bar' and 'a hitman killed my dog' " (ask.metafilter.com).
Pomposity often leads to tortured language. I remember lawyer-turned-sportscaster Howard Cosell, rest his troubled soul, and the way he regularly subjected professional athletes to his cruel and unusual polysyllabic punishment. In general, jocks are spoiled, semi-educated boors, and they know it, so the tug-of-war between them and Cosell was great theater.
At its most sublime, it involved boxing champion Muhammad Ali. He and Howard made a great team, and there was genuine love and trust there. Whatever his faults, Cosell, perhaps at the risk of his own career, had taken up for the draft-evading Ali when the champ was something of a national pariah. (YouTube.com has many wonderful sequences of these two through the years.)
Although there was a good Cosell, all too often we got Bad Howard, neurotically insecure, the one who knew he was kept at arm's length by these great physical geniuses—and resented it. He knew they mocked him, not caring that Cosell had more knowledge of more subjects than all of them put together. So he would sometimes do perverse things, like the time he bullied a poor rookie football player from some Deep South ghetto. Bad Howard said something like: "So, my young friend, in your estimation, did the immensity of the task assigned you, juxtaposed with the metaphysical certainty of your callow demeanor, effectuate a lessened or heightened capacity on your part?"
I'm not kidding. That's pretty close to what Howard said. As the kid listened, his eyes widened with terror and confusion, as if he were being swarmed by a raging horde of ruthless linebackers. I don't recall his answer.
—Tom Stern
Pop Quiz
As we discussed last time, the great writer Elmore Leonard, who died August 20, deplored adverbs. Experienced writers like Leonard prefer strong nouns and verbs. In this quiz, try rewriting each sentence with greater precision and economy. There are no correct answers, but our suggestions may be found in the Answers section.
1. Avoiding wordiness is basically a simple principle of good writing.
2. He went into the room quickly.
3. She was incredibly thrilled by the experience.
4. He said things about us that were viciously harmful and insulting.
5. The committee strongly expressed disapproval of them.
Pop Quiz Answers
1. Avoiding wordiness is a fundamental of good writing.
2. He hurried into the room.
3. The experience elated her.
4. He vilified us.
5. The committee censured them.
To comment on this grammar tip, click on the title.
Posted on Tuesday, September 3, 2013, at 6:53 pm
Leonard's Ten Commandments
The writer Elmore Leonard, who died last week at 87, was the master of hard-bitten prose. He started out as a pulp novelist, and went on to transcend the genre. Since the mid-1950s, more than forty of his works have been adapted for movies and TV, many of them featuring such A-listers as Paul Newman, Clint Eastwood, Robert De Niro, and George Clooney. In his obituary, the Associated Press called the longtime Michigan resident "the Dickens of Detroit, the Chaucer of crime," and said, "Few writers so memorably traveled the low road."
The author's seemingly effortless low-key, economical technique, with its affably nasty edge, has been the envy of many an aspiring novelist. In 2001, he wrote an article for the New York Times that contained ten rules for fiction writers. Anyone interested in the art and craft of writing is urged to seek out this compelling document online. Today we'll deal with a couple of Leonard's precepts.
Rule Three: "Never use a verb other than 'said' to carry dialogue." This is good advice for essayists and journalists, too. Many writers worry that repeating "said" will make them look bad. So they start substituting words like "grumbled, gasped, cautioned, lied" before reaching the end of the line (and of Leonard's patience) with eyesores like "asseverated."
Leonard is stressing that the quote is what matters, and "the verb is the writer sticking his nose in." As William Zinsser says in his fine guide On Writing Well, "The reader's eye skips over 'he said' anyway, so it's not worth a lot of fuss."
Which leads to Rule Four: "Never use an adverb to modify the verb 'said'…To use an adverb this way (or almost any way) is a mortal sin." Many great writers have a similar disdain for adverbs. Mark Twain said, "Adverbs are the tool of the lazy writer." Stephen King, another novelist who has achieved beyond his pulp pedigree, once wrote: "I believe the road to hell is paved with adverbs."
Some will be puzzled by this. But how is The town was completely destroyed or basically destroyed an improvement on The town was destroyed? When you become aware that in most cases, the likes of basically, completely, actually, definitely, and very are unnecessary, you start to understand adverb abhorrence.
One note about very: the distinguished journalist and author William Allen White (1868-1944) once called it "the weakest word in the English language."
Pop Quiz
Despite Elmore Leonard's commandments, some writers may prefer variations on "said" at appropriate times. There are no right answers to this quiz, but with Mr. Leonard in mind, rewrite any sentence below as you wish, and see if your instincts for staying out of the way of a good story are akin to ours.
1. Bob turned to Mary and offered, "You are the loveliest woman at the party."
2. "I came here today and saw a whale," she explained.
3. "Why are you here?" he asked.
"To see you," I replied.
4. "Why, what a jolly surprise," he smiled.
5. "Who is equivalent to he, and whom is equivalent to him," I explained.
Pop Quiz Answers
1. Bob turned to Mary and said, "You are the loveliest woman at the party."
2. "I came here today and saw a whale," she said. (Be careful with explained. In this sentence, nothing is "explained"; it's just a statement of fact.)
3. "Why are you here?" he asked.
"To see you," I replied. CORRECT
4. "Why, what a jolly surprise," he said. (Have you ever heard anyone smile?)
5. "Who is equivalent to he, and whom is equivalent to him," I explained. CORRECT
To comment on this grammar tip, click on the title.
Posted on Monday, August 26, 2013, at 2:22 pm
The Subjunctive Mood
An E-Newsletter fan came across this sentence:
If I were very lucky, I would get the chance to go. She asked, "Shouldn't I be followed by was, not were, since I is singular?"
Let me answer that by asking you a question: Are you old enough to remember the ad jingle that began, "I wish I were an Oscar Mayer wiener…"? These two sentences are both examples of the subjunctive mood, which refers to the expression of a hypothetical, wishful, imaginary, or factually contradictory thought. The subjunctive mood often pairs singular subjects with what we usually think of as plural verbs. The subjunctive is often used in "that," "if," and "wish" clauses.
She requested that he raise his hand.
If I were rich, I'd sail around the world.
He wishes he were in a position to give his employees raises.
Normally, he raise would sound terrible to us. However, in the first example above, where a request or wish is being expressed, he raise is correct. In the next two examples, a thought or wish contrary to fact is being expressed; therefore, were, which we normally think of as a plural verb, is used with the singular subject I.
In general, use the past perfect tense when using the subjunctive mood with verbs besides were.
I wish I had studied more for the test.
It would be better if you had brought the ice cream in a cooler.
Pop Quiz
Select the correct verbs in the following sentences:
1. If I was/were stronger, I would have won that race.
2. I wish he was/were able to come to the party earlier.
3. If she was/were truly your friend, she wouldn't talk behind your back.
4. I wish I practiced/had practiced piano when I was younger.
5. If she had gone/went to the store on Saturday, she would have received a discount.
Pop Quiz Answers
1. If I were stronger, I would have won that race.
2. I wish he were able to come to the party earlier.
3. If she were truly your friend, she wouldn't talk behind your back.
4. I wish I had practiced piano when I was younger.
5. If she had gone to the store on Saturday, she would have received a discount.
To comment on this grammar tip, click on the title.
Posted on Tuesday, March 9, 2010, at 9:11 am
If I Would Have vs. If I Had
Reprinted with permission by Editor Laura Lawless, http://www.elearnenglishlanguage.com/.
When talking about something that didn't happen in the past, many English speakers use the conditional perfect (if I would have done) when they should be using the past perfect (if I had done).
For example, you find out that your brother saw a movie yesterday. You would have liked to see it too, but you hadn't known he was going. To express this, you can use an if-then clause. The correct way to say this is with the past perfect in the "if" clause, and the conditional perfect in the "then" clause:
Correct: If I had known that you were going to the movies, [then] I would have gone too.
The conditional perfect can only go in the "then" clause — it is grammatically incorrect to use the conditional perfect in the "if" clause:
Incorrect: If I would have known that you were going to the movies, I would have gone too.
More examples:
Correct: If I had gotten paid, we could have traveled together.
Correct: Had I gotten paid, we could have traveled together.
Incorrect: If I would have gotten paid, we could have traveled together.
Correct: If you had asked me, I could have helped you.
Correct: Had you asked me, I could have helped you.
Incorrect: If you would have asked me, I could have helped you.
The same mistake occurs with the verb "wish." You can't use the conditional perfect when wishing something had happened; you again need the past perfect.
Correct: I wish I had known.
Incorrect: I wish I would have known.
Correct: I wish you had told me.
Incorrect: I wish you would have told me.
Correct: We wish they had been honest.
Incorrect: We wish they would have been honest.
Pop Quiz
Choose A or B.
1A. If I would have known you were sick, I could have brought you some meals.
1B. If I had known you were sick, I could have brought you some meals.
2A. If you had explained the objective, I could have completed the assignment sooner.
2B. If you would have explained the objective, I could have completed the assignment sooner.
3A. I wish it would have gone differently.
3B. I wish it had gone differently.
4A. We wish the team had scored more goals.
4B. We wish the team would have scored more goals.
Pop Quiz Answers
1B. If I had known you were sick, I could have brought you some meals.
2A. If you had explained the objective, I could have completed the assignment sooner.
3B. I wish it had gone differently.
4A. We wish the team had scored more goals.
To comment on this grammar tip, click on the title.
Posted on Saturday, April 4, 2009, at 7:25 pm
Nouns Can Become Verbs
E-Newsletter reader Clifford A. recently wrote:
My wife says she texted our daughter.
I say, I sent her a text message.
Is texted an accepted usage?
English allows many nouns to become verbs. We can table a motion, salt our food, and water our plants. Particularly in the realm of developing technology, new usages are common, and even nouns that never used to be verbs have taken on new roles. Text as a verb is accepted usage.
More Examples:
Children, please don't horse around.
Have you ever googled your name to see what came up?
The race car snaked around the curves.
Xerox three copies of that letter before the meeting at noon.
To comment on this grammar tip, click on the title.
Posted on Tuesday, February 24, 2009, at 10:11 am

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Why I believe the Bible to be invalid as a citation for any argument...
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New King James Version.
Deuteronomy 8:
11Beware that you do not forget the Lord your God by not keeping His commandments, His precepts, and His statutes which I command you today,
12Lest when you have eaten and are full, and have built goodly houses and live in them,
13And when your herds and flocks multiply and your silver and gold is multiplied and all you have is multiplied,
14Then your [minds and] hearts be lifted up and you forget the Lord your God, Who brought you out of the land of Egypt, out of the house of bondage,
15Who led you through the great and terrible wilderness, with its fiery serpents and scorpions and thirsty ground where there was no water, but Who brought you forth water out of the flinty rock,
16Who fed you in the wilderness with manna, which your fathers did not know, that He might humble you and test you, to do you good in the end.
17And beware lest you say in your [mind and] heart, My power and the might of my hand have gotten me this wealth.
18But you shall [earnestly] remember the Lord your God, for it is He Who gives you power to get wealth, that He may establish His covenant which He swore to your fathers, as it is this day.
19And if you forget the Lord your God and walk after other gods and serve them and worship them, I testify against you this day that you shall surely perish.
20Like the nations which the Lord makes to perish before you, so shall you perish, because you would not obey the voice of the Lord your God.
Anonymous Coward 602429
Words to a certain people at a certain time in the past. Sometimes the words have an enduring message, but often it is more like a history of something in the past. Taken out of the historical context, many false teachings have come from the Bible. There are many truths that we can live by today, but some of the Bible is a record of what was said and done in the past.
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This Is The Rebel Flag, "You're Either Free Or You're Not."
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text:
WASHINGTON (AP) — Defense Secretary Leon E. Panetta said Tuesday he was awaiting details from Marine Corps Gen. John R. Allen, the top commander in Afghanistan, on his plan for bringing home the remaining 23,000 troops sent to Afghanistan during the 2010 surge.
After the weekend's mass killing of Afghan civilians in the southern province of Kandahar, allegedly by an Army staff sergeant, Mr. Panetta and other top administration officials said it would have no effect on the war strategy. That does not mean, however, that the planned troop withdrawal won't be accelerated at some stage.
Mr. Panetta, speaking to reporters on a flight to Bishkek, Kyrgyzstan, said that despite recent setbacks, including the burning of Korans by U.S. soldiers last month and the civilian massacre over the weekend, there has been no change in plans to complete a troop withdrawal by the end of 2014.
Gen. Allen said on Monday that about 90,000 U.S. troops are in Afghanistan now. He said he plans to bring out 23,000 of those by the end of September, as required by President Obama, but Mr. Panetta has yet to endorse that exact schedule.
Mr. Obama has given Gen. Allen no orders on specific troop withdrawals beyond September, except to say there will be a "steady pace" of withdrawals between now and the end of 2014, when Afghan forces are to be fully in charge of the country's security.
The New York Times reported Tuesday that the administration is considering a range of options for further troop reductions after September. One option is for at least 10,000 more to come home by the end of December and then 10,000 to 20,000 more by June 2013, the Times reported, citing unnamed administration officials.
Asked about the Times report, Pentagon press secretary George Little, who is traveling with Mr. Panetta, said: "The analysis on drawdown scenarios isn't yet complete, and the secretary has not been presented with options. It's premature to speculate on any drawdowns beyond those associated with U.S. surge forces in Afghanistan."
Earlier, Mr. Panetta said he had not yet seen details of Gen. Allen's plan for a drawdown this summer.
"What I am awaiting are General Allen's plans with regards to taking down the remaining 23,000 from the surge," Mr. Panetta said, "and we'll review those plans."
Associated Press writer Lolita C. Baldor contributed to this report from Bishkek, Kyrgyzstan.
Copyright 2015 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.


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Originally written on College Football Universe | Last updated 3/26/13
ESPN's Mel Kiper has long been looked at as the guru of NFL mock drafts. A look at his big board has some similarities to that of CFU's, but also some big differences. Todd McShay of ESPN and Scouts Inc. has Texas A&M offensive tackle Luke Joeckel as the top-rated player, like CFU. But Kiper went with Florida defensive tackle Sharrif Floyd, who McShay has second and I rated sixth overall. Kiper rated Joeckel as his fourth-best prospect.My reasons are simple. I really like Floyd's strength, versatility and upside, but I just like the explosiveness and athleticism of Missouri's Sheldon Richardson more. That's why Richardson, whom I've known since his junior year of high school, is rated two spots ahead of Floyd. Kiper ranks Richardson, a 6-foot-2, 294-pound St. Louis native, at 12th. McShay completely devalues Richardson's talent by having him 15th on the Scouts, Inc. big board.We all agree on Central Michigan offensive tackle Eric Fisher as the third-best prospect. At No. 2, wher
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Why do online shoppers keep returning clothes?
There's more to it than you thinkJune 30, 2015 9:42
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Saudi's Mobily to reissue 2014, Q1 2015 results after regulator probe
Dubai Holding appoints new managing director, CEO
HSBC Bank Oman agrees to sell Pakistan business to Meezan Bank
European tour operators evacuate thousands from Tunisia after attack
French group to invest at least $150 mln in Saudi's Kingdom Holding
Gold ticks up from 2-week low as market eyes Greece
Car bomb aimed at UAE officials kills three Somali soldiers in Mogadishu
Abu Dhabi's Etisalat jumps 13.8 pct on looser ownership curbs
RSE, Qatar teaming up to buy stake in Formula One
Qatar building boom proves a challenge for foreign construction firms
Facebook has been summoned by the French government to provide an explanation for the 'privacy breach' but the company says there has been none
September 25, 2012 2:50 by Muhammad Aldalou
The century old argument of 'if you have nothing to hide you have nothing to be nervous about' is really starting to wear thin, particularly with Facebook users. What would you do if two years worth of privately sent messages were suddenly published on the public newsfeed for everyone to see? It's a scary thought to many, as Kipp would imagine, and having something to hide has little to do with it.
At any rate, that was the question that many unknowing France-based users were slapped with when (allegedly) years worth of private messages were publicly revealed.
Kipp sticks to "allegedly" because while many users swiftly jumped to their Twitter accounts, comment sections and assorted blogs to declare and swear that it did in fact happen, Facebook's management insist that after a thorough inspection, they conclusively discovered that it was merely public posts from years ago, not private messages. But Kipp wonders, does that really make it any less of a shocking violation?
"A small number of users raised concerns after what they believed to be private messages appeared on their Timeline. Our engineers investigated these reports and found that the messages were older wall posts that had always been visible on the users' profile pages. Facebook is satisfied that there has been no breach of user privacy," said Facebook in an email statement.
While the multi-billion dollar company appears to be satisfied, doesn't the fact that Facebook managers were summoned by the French government give more validity or body to this alleged rumour? The government demanded 'clear and transparent explanations without delay'.
But, that isn't even the point is it? Two years ago, security features that exist on the social media site now didn't then, nor was there a timeline template or the option of sharing specific posts only with specific people. All those features had rolled in because of user demand, ironically. So if years worth of posts were suddenly rehashed and made visible to everyone on your current list, how can the company still stand by their 'no breach of user privacy' statement?
Sure, one may have made some public posts years ago, but a lot of things could and probably did change since then. The number of friends on a person's list, people that he/she perhaps wouldn't want to read said posts, etc. In a nutshell, taking a post, public or not, produced explicitly or implicitly out of its context, is still seen by many as a violation of social norms.
Do you think this is an overreaction from the users' part or do you feel that, whether it was private messages or public posts, it is a breach of privacy?
Intel announces winners of Intel Challenge Levant
September 25 2012
World economy shifting from West to East through Sheikh Zayed Road - SA Ambassador
September 25 2012


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A popular Oriental stir fry recipe with the crunchiness of cashew nuts and sweetness of mangoes. It is also known as 'Ga Xao Hat Dieu'.
Cashew nut and milk based sweet traditionally served at special occasions, topped by silver leaf.
A sharp and nutty sauce of cashews and rocket leaves.
Make delicious kothimbir vadis at home with the richness of cashew nuts. A classic Maharashtrian snack.
Easy-breezy and so delicious. Semolina halwa made with dry coconut, raisins, almonds and cashew nuts.
Nutty Indian sweet and a variation to the popular dessert, Mysore Paak, this version is made with cashew nut, besan and ghee. This sweet is native to Karnataka and is known for its softness ...
People with a sweet tooth, here is an easy chocolate pizza recipe for you. This pizza has chocolate with nuts and is topped with strawberries. Yummy!
This salad has it all. The sweetness of the mango, the crunchiness of the pear and nuts, the leafy greens and a cheesy dressing.
Rattan Manjusha and Ultey Tawe Ka Paratha
Paneer koftas, stuffed with nuts, honey and seasoning are dipped in a creamy tomato gravy and served with parantha cooked on an upturned tawa.
Rice cooked in saffron, milk, nuts and cardamom.
During any big festival, especially Diwali, we're hard-wired to crave everything sweet and everything nutty. Crunchy walnuts, rugged almonds, nutty cashews, creamy pistachios and bulky chironji nuts set the mood of the occasion. They feature ...


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LeVian Aquamarine Ring 1/4 ct tw Diamonds 14K Vanilla Gold
This irresistible ring from Le Vian® features an oval Sea Blue Aquamarine® traced in round sparkling Vanilla Diamonds® and a splash of Blueberry Diamonds®. Styled in 14K Vanilla Gold®, the ring has a total diamond weight of 1/4 carat. Blueberry Diamonds® are treated to permanently create the intense blue color. Le Vian®. Discover the Legend. Diamond Total Carat Weight may range from .23 - .28 carats. Gently clean by rinsing in warm water and drying with a soft cloth.
No price available.


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When he reached the age of 30, Vonnie Holliday began terming himself as a dinosaur in the young man's world which is the National Football League.
CHARLESTON -- The Charleston RiverDogs will salute the United States Postal Service's newest stamp and the history of the Negro Leagues during a special Larry Doby Heritage Weekend when the club hosts the Greenville Drive at Joseph P. Riley, Jr. Park in a two-day celebration on Saturday and Sunday, July 14-15.
As he looked into purchasing an American Basketball Association franchise, the first person Devin Lee told as to his plans was his wife and former Lugoff-Elgin track and basketball player, Nikia Knox-Lee.
-I (Camden, S.C.) sports editor
Brock Robinson has been the Kershaw County Junior Post 17's money pitcher all season long. Monday night, Robinson helped KC cash in.
SUMTER -- With a League III title already in hand and the American Legion baseball state playoffs waiting next week, the Sumter P-15's could have come out and laid an egg in its final regular-season game against Kershaw County on Thursday at Riley Park.
The KC Junior P-17ers, the League IV champions, will take their 13-2 record into tonight's first game of the best-of-five state playoff series against visiting Marlboro County (7-8).
Having already conquered the state of South Carolina, the Kershaw County-based Lite 'em Up girls' fast-pitch softball team is ready to take on the world.
Having already locked down second place in the League IV American Legion baseball race, Lexington forfeited Tuesday night's scheduled road game against Kershaw County Post 17. The contest was to have been the final league contest for both teams.
As he and his team got off the bus for Monday night's game at Lexington, Kershaw County American Legion head coach Craig Smith saw and heard the athletic director of the host team giving members of the Post 7 squad a talk on sportsmanship.
Funny how one simple flip of the coin can change a team's entire disposition.
KC Northern overcame an early game Bishopville grand slam to score a 15-9 victory to win the District 5 Sub-District A Dixie Youth Baseball Tournament on Friday night at Woodward Park in Camden.
Monday: Post 17 at Lexington (7 p.m.)
With their slim state playoff chances hanging tenuously in the balance, Kershaw County Post 17 picked the wrong team with which to finish out the League IV regular season.
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There is little known regarding which teams will be in this week's state American Legion baseball playoffs or where they are going since there was no bracket to be found as to the pairings.
Turning what was to have been a doubleheader of baseball into, basically, one single game, Kershaw County Post 17 cemented its second-place finish in League III by sweeping Wednesday's pair of games with visiting Manning-Santee.
At first, it started out with his signing autographs and posing for pictures with youngsters attending last week's annual Vonnie Holliday Football Camp in Camden.
Standing on the stage at Lugoff-Elgin High School as a participant in the 1995 Mr. L-E Pageant, Monte Lee was asked by the moderator of the competition where he saw himself in 10 years.
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Gram Likes It!
January 28, 2013 6:00 AM
Fresh Mornings
Listen mornings 6-10amRead More
Today, we had a new listener call in to try to figure out what lyrics Gram was rockin' while cooking up some chicken soup this morning.
Find out how they did below!
Here's How It Works…
Producer Craig's Gram will read some lyrics from one of today's hit songs that she's been jammin' on while doing the dishes, laundry and gardening. We'll pick a caller to try to guess what song it is in order to win the prize of the day!
Contact the Jim & Kim Show:
- Email Producer Craig at: email@example.com >
- Give Jim Douglas Golf Tips at: firstname.lastname@example.com >
- Wake Up Kim Berk at 3am at: email@example.com >
- 'Like' Jim & Kim On Facebook >
- Bios: Get To Know Jim & Kim and Craig Too >
Read More On Fresh1027.com:
- Demi Lovato Will Be Iggy Azalea's Bridesmaid And She Will Look Good Doing It
- Jim Carrey Calls California Governor a 'Fascist' After Passing Mandatory Vaccination Bill
- Demi Lovato is Keeping It Hot With New Single 'Cool For The Summer'
- 21 Wildly Different Songs All Named 'Freedom'
- You Can't Remake 'Back to the Future' Until Robert Zemeckis Dies


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Use our new superlist posting interface and quickly create exceptional, media-rich buzz posts.
I have been doing this. A little bit slow but very effective! :-D
alexander2 is a BuzzFeed user and their posts have not been vetted or endorsed by BuzzFeed's editorial staff. BuzzFeed Community is a place where anyone can post awesome lists and creations. Learn more or post your buzz!
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This property allows you to book online with a credit card. After submitting a reservation request, the owner or manager has 24 hours to accept, at which time your card will be charged and you will receive an email confirmation
Recent St Maarten reviews
"I stayed with my husband and teenage son during first week of April 2015. We didnt rent a car and were able to move around with ease since the apt is in a centric location. We walked to Mullet Bay, Sunset Grill, and Maho village. The apt has all the basics and much more. We will be back!"Guest: Annette Date of Stay: March 2015 Review Submitted: April 7, 2015View listing
"My wife and I have visited St. Martin (7) years in a row. This is the 1st time we have stayed with Bruce and Joyce. We are glad to say we have found a place that we will return to next year and many years after that. We had a wonderful time and a perfect stay. No longer will we be searching for a place to stay. This place is "perfect"."Guest: Brad and Lisa Date of Stay: April 2015 Review Submitted: April 29, 2015View listing
"Santa Clara is a beautiful quiet home nestled in your very own paradise garden. The home is wonderfully decorated but still provides the comfort factor that one needs when traveling with children. Three bedrooms and three private baths gave us all room to spread out. The kitchen was well equipped and there is room to dine both inside and outside the house. We loved the pool and the covered cabana area. It gave shade from the sun but still allowed us to watch our son play in the water. Comfortable sunning chairs are around the patio and there is even a convenient outdoor restroom. The large TV in the living room gave access to quite a few channels but remember to bring DVDs if you cannot follow along in French The house is convenient to both Cupecoy and Marigold within a few minutes drive, and easily accessible to all areas of the islands as well. We frequented several restaurants in the area (Fig is wonderful) and also cooked a few meals in the kitchen when our young son was too tired to go out. We hope to return again to Santa Clara in the future. Thank you Greg & Lilly for everything."Guest: Anonymous Date of Stay: February 2015 Review Submitted: March 8, 2015View listing
"Our family holiday getaway to St Martin was perfect, in no small part thanks to Veronique and the lovely Casa Azul. Can't say enough good things about the process of renting, arrival, settling in, extras (like making reservations for us for New Year's Eve), peace and quiet, and an amazing view. All our expectations were exceeded. Everyone was comfortable and in the island mood. The perfect slice of heaven for a great, relaxing escape."Guest: Nancy C. Date of Stay: December 2014 Review Submitted: January 21, 2015View listing
St Maarten Travel Tips
St. Maarten Resorts Present a Personal Holiday
Do you want a personal stay, where it feels like the owners have set everything up just for you? If you want a kitchen for home-cooked meals, a centrally located home, and the sunrise outside your bedroom window then St. Maarten lodging is precisely what you need. Act now as every year, more and more people find the little gem that holds St. Maarten resorts. You will have your pick of St. Maarten rentals along the coastline on Antilles.
The Antilles and St. Maarten Lodging
Antilles is a large island in the Caribbean waiting to greet you with perfect St. Maarten rentals. The island is owned by the French and the Dutch which peacefully share the land. St. Maarten is the Dutch side of Antilles, which is also the smaller portion of the landmass. The French spelling of St. Maarten is St. Martin, which helps you locate the proper St. Maarten lodging when you plan your vacation. The climate at St. Maarten resorts is a sunny and balmy 80 degrees Fahrenheit virtually year-round, so you can visit at any time of year.
St. Maarten Rentals near Ruby Bute's Studio
A true delight for many vacationers to St. Maarten rentals is visiting Ruby Bute, one of the most famous island artists. She creates botanical landscapes and images of island life through her paintings and poetry. Her studio and gallery are open in Marigot, north of downtown near Friar's Bay. You might want to call first to make sure she is welcoming visitors for the day you plan the trip, and bring local currency to come home with one of her reasonably priced prints.
Island Gambling at St. Maarten Resorts
St. Maarten lodging is conveniently located near the island's 12 casinos. All of these casinos are located on the Dutch side and with gaming in the European mode. Spend your late nights inside the St. Maarten resorts' casinos, and your days along the various beaches.


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Jarett Andretti carrying on the family tradition
Feb 28, 2014, 12:17 PM EDT
Another member of the fabled Andretti clan is preparing to carry on and continue the family tradition.
Jarett Andretti – son of John, cousin of Marco, nephew of Michael, grandson of Aldo and great nephew of Mario – is preparing for his first full season of competition in both the USAC National Sprint Car and Silver Crown Series.
Jarett, 21, will race for uncle Michael's Andretti Autosport Short Track subsidiary, making him a third-generation racer. The team expects to compete in more than 50 races this season.
"Like all drivers, I think about the racing schedule that I may be doing coming into a new season," Jarett said. "Obviously, we all want to race as much as possible and this year, I could not have wished for a better lineup of races.
"I will be competing all the time in a variety of cars against the toughest competitors in short track racing in the country. I'm really looking forward to this year."
Although this is his first full-time ride, the youngest racing Andretti is far from being a neophyte when it comes to being around a racetrack. He's actually entering his fourth season behind the wheel of competitive racing.
He's steadily progressed in several series, including winning championships in go-karts and the USAC Eastern Ignite Pavement Series. Last season, he competed part-time in Sprint Cars and Silver Crown Cars, earning Rookie of the Year honors in the Sprint Car category at Lawrenceburg (Ind.) Speedway, in the shadow of the famous Indianapolis Motor Speedway.
Andretti will drive the Superior Auto Sprint Car in all Midwest USAC races. He will also be behind the wheel of the No.4 Window World Silver Crown car on pavement and the No.14 McQuinn Silver Crown car at all of the dirt track Silver Crown races.
For more information on the latest addition to the Andretti family team of racers, check out Jarett's web site, JarettAndretti.com, or catch him on Twitter @JarettAndretti.
Follow me @JerryBonkowski
- indycar02 - Feb 28, 2014 at 2:06 PM
im supprised he isnt in formula cars (like marco was), remember what happened to jason lefler n tony stewart.
- midtec2005 - Mar 2, 2014 at 4:42 PM
Yes, every time someone straps into a sprint car they are killed or maimed *facepalm*
- cfischeraz - Feb 28, 2014 at 2:42 PM
Aldo, not also.
- Jerry Bonkowski - Feb 28, 2014 at 2:47 PM
That's what happens when your finger slips from the D to the S. Thanks for the catch!
- indycar02 - Feb 28, 2014 at 8:44 PM
what the ? ! ?……..
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Napoli keeper Navarro staying with River Plate
The agent of Napoli goalkeeper Nicolas Navarro has ruled out a return to Italy in January.
The young Argentine is currently playing on-loan at River Plate.
Navarro's agent, Gustavo Ghezzi, said: "He wants to continue playing for River Plate, which has a new president, let's see how things go."