text: CONTROVERSY To Treat or Not to Treat in Clinically Isolated Syndrome The decision whether to treat or not to treat patients presenting with a clinically isolated syndrome suggestive of multiple sclerosis (MS) can be a difficult one. If the results of magnetic resonance imaging (MRI) are normal, most clinicians would not treat, as the risk of development of MS is low. If the MRI is abnormal, however, the decision is considerably more difficult. At present, we do not have any good markers that would allow us to deter- mine which individuals will go on to develop MS and which individuals will remain stable. An advantage of early treatment is a 15% to 20% further reduction in attack frequency over and above the approximately 30% decrease that occurs with later treatment. This has been a consistent finding with early treat- ment with the interferons and glatiramer acetate. Nevertheless, with early treatment we are subjecting many patients to a regimen that will not help them in order to improve the outcome in those who will develop clinically definite MS. This "medicalizes" those patients, who will suffer the same side effects as those who need the medication. On the other hand, the placebo patients from the phase 3 trials who were treated with their second attack sub- sequently have more attacks than those treated early, and probably more disability. The long-term subcutaneous interferon beta-1b (Betaseron) results showed a much higher 17-year mortality rate in those receiving placebo than in those treated with either low-dose or high-dose Betaseron in the phase 3 trial. The following two articles by Richard A. Rudick (Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH) and David A. Cottrell (Frenchay Hospital, Bristol, UK), respectively, present both sides of this ongoing controversy. —Robert M. Herndon, MD Editor Emeritus and Controversies Editor The Case for Early Treatment of Clinically Isolated Syndrome with Disease-Modifying Drugs Richard A. Rudick, MD E arly and continuous therapy with disease-mod- ment because they have mild MS. 2) Delaying treat- ifying drugs (DMDs) is advisable for patients ment a few years to monitor and select patients for with clinically isolated syndrome (CIS) at high DMD therapy is safe. 3) There is no evidence that early risk of multiple sclerosis (MS), and for patients with and continuous treatment with DMDs translates into established early relapsing-remitting MS (RRMS). long-term benefits. 4) Early and continuous treatment is too expensive and carries unnecessary patient burden Objections to this position include the following: 1) and risk. Because health-care resources are finite and Some patients do not need early and continuous treat- MS drugs are expensive, the last of these objections From the Mellen Center for Multiple Sclerosis Treatment and may have merit. Estimating the financial benefits of Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, DMDs is difficult, because financial costs are front- USA. Correspondence: Richard A. Rudick, MD, Mellen Center loaded, while financial benefits are delayed and are sub- U10, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195; e-mail: email@example.com. ject to imprecise estimates of preventable health-care International Journal of MS Care 99 Controversy costs. Also, support, education, advocacy, rehabilita- inflammation, which has been linked to axonal transec- tion, and symptomatic therapy have many benefits, tion. Transected axons are abundant in acute MS and some of these approaches are relatively inexpensive plaques and at the inflammatory edges of chronic compared with DMDs. Cost-effectiveness of DMDs active lesions, even in patients with short disease dura- relative to other approaches to MS therapy is an impor- tion.5 Transected axons are terminally injured and will tant debate, but in this article, I will assume that degenerate, contributing to abnormalities in the nor- mal-appearing white matter observed on MRI studies.6 DMDs are accessible and affordable and will focus on Some gadolinium-enhancing lesions leave persistent the scientific and clinical rationale for early treatment. black holes, which represent areas of reduced axonal Four fundamental considerations support my rec- density.7 ommendation for early diagnosis and continuous dis- These observations demonstrate that inflamma- ease treatment. tion within acute MS lesions irreversibly damages 1. MS evolves to a disabling disease in a significant central nervous system (CNS) tissue, suggesting an proportion of affected individuals; benign MS exists but ongoing destructive pathologic process during the cannot be accurately predicted early in the disease. Wein- course of RRMS. Not surprisingly, longitudinal shenker and colleagues 1 reported that MS patients MRI studies demonstrated accelerated brain atrophy required assistance with walking a median of 15 years in MS patients.8,9 Brain volumes decline five to eight from their diagnosis. Confavreux and colleagues 2 times faster than in healthy, age-matched controls, reported that once MS patients experienced limitations reflecting increasing loss of myelin and axons over the in ambulation, they could expect progressively increas- course of the disease. This process begins very early in ing disability over time. Clinical experience confirms MS. Rapid rates of brain atrophy have been observed these observations. Middle age brings progressive walk- in CIS patients who convert to MS,10,11 and rapid brain ing problems for many MS patients. Once walking atrophy continues throughout the disease. Like all dis- problems begin, gradual deterioration is the rule, not ease-severity measures, atrophy rates vary across MS the exception. Undoubtedly some patients have mild patients, and the rate of atrophy during RRMS is only MS, and some—perhaps 20% of the total—never expe- weakly correlated with relapses or Expanded Disability rience disability from their disease. However, some Status Scale (EDSS) score.12 This suggests that progres- patients classified as benign after 10 years progress to sive loss of brain tissue may be clinically inapparent higher levels of disability after another 10 years.3 Also, during early stages of the disease. Brain atrophy during some patients classified as having "benign MS" have RRMS is highly relevant, however, as it has been shown significant cognitive impairment. Thus the definition to predict future ambulatory13 and cognitive9 disability. and diagnosis of benign MS are problematic. The real Accelerated gray matter atrophy occurs in patients at all problem, however, is that benign MS can be diagnosed stages of MS as well14 and correlates better with disabili- accurately only in retrospect. No precise markers of ty than other MRI measures.11 benign MS exist that can be applied at the beginning of The picture emerges of a disease that is pathologically the disease, or within a few years. Patients are not well active from onset, in which CNS tissue may be dam- served by an imprecise prediction that they might have aged or destroyed without obvious clinical manifesta- benign MS. Delaying treatment in patients who may tions during early disease stages. Over time, with cumu- have benign MS will inevitably result in lost opportuni- lative brain tissue injury and the additive effects of ties for many individuals who need treatment. aging, a threshold is surpassed beyond which neurologic 2. Irreversible axon and myelin injury occurs early in function fails and progressive disability ensues. This is the course of MS and is mostly subclinical but leads to sec- the likely basis for SPMS. If this is the correct sequence ondary progressive MS (SPMS). Longitudinal magnetic of events, then waiting for progressive disability before resonance imaging (MRI) studies have demonstrated a treating is inappropriate. This model supports the need high frequency of new subclinical brain lesions, indi- for early preventive therapy. cating that MS is frequently active without clinical dis- 3. Early treatment reduces brain inflammation, is neu- ease manifestations.4 New MRI lesions reflect tissue roprotective, and delays SPMS. Phase 3 trials of subcuta- International Journal of MS Care 100 Controversy neous interferon beta-1b (IFNβ-1b) (Betaseron), 15 (Rebif ) persisted at 4 years. Patients with continuous intramuscular interferon beta-1a (IFNβ-1a) (Avonex),16 treatment for 4 years were significantly better than subcutaneous IFNβ-1a (Rebif ),17 and subcutaneous patients with an initial 2-year treatment with place- glatiramer acetate (Copaxone)18 have demonstrated a bo.28,29 Assessment of patients from the placebo-con- reduction in relapse rate of approximately 30% in trolled study of intramuscular IFNβ-1a (Avonex) RRMS. The beneficial effect on new MRI lesions is showed that treatment with IFNβ-1a rather than place- greater. In some trials, reduced disability progression bo for 2 years led to better patient outcomes at 8 years, measured using the EDSS was also observed, 16,17 even though all patients were treated about the same although some argue that permanent disability is diffi- between 2 and 8 years.30 A 5-year extension of the cult to measure in early MS because most patients do CHAMPS study showed a persistent benefit for the not become significantly disabled, the EDSS may patients originally treated with IFNβ-1a (Avonex), even measure impairment rather than disability at the low though placebo patients were switched to IFNβ-1a end of the scale, and some of the change may be noise after converting to clinically definite MS (CDMS).31 in the measure or reversible change.19 However, some Third, studies of IFNβ and glatiramer acetate have studies12,20,21 demonstrated reduced rates of brain atro- been largely negative in patients with SPMS; thus, no phy, clearly indicating that therapy during the RRMS drugs are approved for treatment of SPMS, because no stage can inhibit irreversible brain tissue destruction. drug has established efficacy in slowing disability pro- This was also seen in the AFFIRM study, in which gression once patients enter this stage of the disease. natalizumab (Tysabri) significantly reduced brain atro- Brain atrophy studies are consistent with the clinical phy in the second year of the clinical trial.22 Because findings. In contrast to RRMS, there are no examples the rate of brain atrophy has been linked to future dis- of treatment interventions that slow the rate of atrophy ability, it is reasonable to speculate that reduced brain in SPMS.32,33 It seems that patients become refractory atrophy during RRMS will translate into delayed tran- to treatment at later stages of MS. sition to SPMS. This was recently reported in a longi- Collectively, these studies suggest a "window of tudinal study.23 opportunity" for treating MS. Some prominent thought 4. Delayed treatment is less effective than early treat- leaders have proposed very early, aggressive immune ment, and no treatment is effective once the patient transi- suppression in patients with relapsing MS, with favor- tions to SPMS. What is the harm in waiting to decide able early results.34 Although the jury is still out on the about DMDs in MS patients? The problem with this benefits and risks of very aggressive, early treatment, strategy is that early treatment appears to be more continuous treatment of MS patients early in the disease effective than delayed treatment. First, studies using the with currently available, safe DMDs is clearly beneficial same drug at different disease stages have shown consis- and advisable. tently higher therapeutic effects in earlier stages of dis- ease. Studies of IFNβ and glatiramir acetate have Financial Disclosures: Dr. Rudick has received consulting fees shown that these agents reduce relapse rates by about from Millennium, Novartis, Teva Neuroscience, Wyeth Pharmaceuti- 30% in established RRMS but by about 50% in cals, Biogen Idec, and Genzyme-Bayer. patients with CIS.24-26 Interferon beta-1a reduces sus- References tained EDSS worsening by about 40% in RRMS, but 1. Weinshenker BG, Bass B, Rice GP, et al. 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Coles AJ, Compston DA, Selmaj KW, et al. Alemtuzumab vs. interfer- Disability as an outcome in MS clinical trials. Neurology. 2008;71: on beta-1a in early multiple sclerosis. N Engl J Med. 2008;359: 624–631. 1786–1801. International Journal of MS Care 102 Controversy The Case for Delaying Treatment of Clinically Isolated Syndrome David A. Cottrell, MB ChB, MRCP, BSc, PhD A s a practicing neurologist in the United treatment group, compared with 5% of the delayed Kingdom with a special interest in multiple treatment group, having entered the progressive phase sclerosis (MS), I often prescribe interferon over the 10 years of follow-up. This was despite a beta (IFNβ) and glatiramer acetate for patients with maintained 10-year risk reduction in the number of relapsing-remitting MS (RRMS) and, if relapses are patients developing clinically definite MS (CDMS) in prominent, in patients with secondary progressive MS. those receiving immediate treatment. The results from The decision whether to start one of these agents is extension trials are, however, very difficult to interpret made with the patient after we have discussed the avail- because of their significant dropout rates, the nature of able evidence of efficacy and the potential side-effect crossover trials, and problems with validation using profiles of these therapies. small changes in the EDSS as a measure of unremitting An early, safe, tolerable treatment that, most impor- disability.4 tantly, has long-term efficacy is highly desirable for I remain unconvinced by the data presented from newly presenting patients, their families, and MS spe- these trials that initiating either IFNβ or glatiramer cialists. Hence I have followed the evolving industry- acetate after a patient's first clinical episode of demyeli- sponsored clinical trials of drug treatment for patients nation is in the patient's best interests. I outline my with clinically isolated syndrome (CIS) with interest. reasoning for this position below. The evidence for commencing IFNβ or glatiramer Potential Failure of Trial Blinding acetate in patients presenting with CIS is based on data The BENEFIT trial acknowledges that blinding was from the ETOMS, CHAMPS, and BENEFIT studies, unsuccessful, with 67% of patients correctly guessing as well as the recently completed but as yet unpub- that they were receiving the active drug, versus 51% in lished PRECISE study.1-3 Each of these trials random- the placebo cohort.3 Unfortunately, the other CIS trial ized patients with "positive" baseline brain magnetic reports do not provide this essential information on the resonance imaging (MRI) studies to either placebo or potential for failure of blinding. Both CHAMPS and IFNβ (at a range of dosages) or glatiramer acetate ETOMS, however, do report a significantly higher inci- (PRECISE). All four treatment cohorts show similar dence of well-recognized and highly publicized side rates of relapse reduction in the region of approximate- effects (as also seen in the BENEFIT trial) in the IFNβ ly 15% over a 2-year period but no significant alter- group compared with the placebo group, including ation in disability as compared with the placebo injection-site reactions (60% vs 12% in ETOMS), flu- cohorts. Indeed, the longest extension trial presented to like symptoms (54% vs 26% in CHAMPS), and date, the CHAMPIONS 10-year data (American Acad- depression (20% vs 13% in CHAMPS).1,2 emy of Neurology, 2009) continues to show no signifi- The side-effect profiles of IFNβ and glatiramer cant difference in either the Expanded Disability Status acetate are readily available to all with Internet access. Scale (EDSS) or Multiple Sclerosis Functional Com- Therefore, loss of trial blinding is perhaps unavoidable posite (MSFC) between the immediate and delayed given the frequently unpleasant side effects that often treatment cohorts. These trial data also demonstrate a accompany these agents. slightly worrying trend, with 14% of the immediate It is certainly widely recognized that relapse rates are not immune to placebo effects. Indeed, significant From the Department of Neurology, Frenchay Hospital, Bristol, Unit- apparent positive effects on relapse rates occur regularly ed Kingdom. Correspondence: David A. Cottrell, MB ChB, MRCP, BSc, PhD, Department of Neurology, Frenchay Hospital, Bristol, in the placebo arms of recent RRMS clinical trials. If BS16 1LE, United Kingdom; e-mail: email@example.com. blinding is not successfully achieved, it does call into International Journal of MS Care 103 Controversy question the validity of such trials, particularly those not due to pharmacologic intervention, as only 4 of the with small apparent treatment effects. Could this lack 107 patients who were followed up (including patients of blinding explain the remarkably consistent apparent with normal as well as abnormal baseline MRI studies) clinical treatment effect seen despite the wide range of were treated with disease-modifying therapies at some IFNβ dosages used in the CIS trials (22 µg once weekly point over the 20 years of follow-up. This natural histo- to 250 µg on alternate days), not to mention the simi- ry of CIS in patients with abnormal baseline MRI stud- lar response rate seen with the unrelated glatiramer ies is in striking contrast to the median EDSS score of 8 acetate? found in the entire London, Ontario, cohort at 20.6 If not, these trials suggest that there is no dose years from the time of first clinical onset, or the median response to IFNβ in the reduction of relapse rates in EDSS score of 7 found at 20 years from the first event CIS. Pharmacologically, it is quite unusual to see no in those patients who presented with RRMS.7 apparent dose response to an active treatment. Although In addition, ETOMS reported a surprisingly low I accept that this is unlikely to be the full explanation annual relapse rate (ARR): 0.43/year in the placebo for the trial results and certainly could not explain the arm despite enrolling a highly selected patient group MRI findings, I believe that all such trials in cohorts of with MRIs laden with demyelination (median T2 load, MS patients should be assessed for blinding to aid clini- 24).1 A review of the data provided in the CHAMPS cians in the interpretation of such important data. and BENEFIT trials suggests that the relapse rates in the placebo arms of these CIS trials do not differ sub- Natural History of CIS stantially from that in ETOMS. These ARRs are con- The principal aim of starting a treatment early in siderably lower than those in the original RRMS piv- the course of MS must be to avoid long-term disabili- otal studies, which ranged from 0.9 to 1.28. Given that ty. We are all well versed in the natural history of these patients presumably have already had numerous CDMS, but the natural history of CIS, with or with- episodes of clinically silent demyelination, as evidenced out MRI evidence of disseminated demyelination, can- by their MRI brain scans, could these studies have not be assumed to be the same. inadvertently selected a more benign clinical pheno- The London, Ontario, and Lyon long-term prospec- type? We have all seen highly abnormal MRI scans sug- tive natural history cohort studies both enrolled patients gestive of demyelination in patients with either no diagnosed using Poser's criteria. These cohorts therefore symptoms suggestive of MS or surprisingly little in the represent the natural history of patients who go on to way of disability. Certainly despite their significant have a second clinical episode of disability or progres- median T2 lesion loads these trial cohorts show surpris- sive disease. The natural history of CIS has not been ingly little in the way of disability as measured by the studied to the same extent. Two smaller long-term CIS EDSS either at the beginning or end of the CIS trials, follow-up trials, however, suggest that as many as 20% in addition to their low clinical relapse rates. of patients with CIS will remain free of any further Many would argue that we need not wait for the new neurologic symptoms suggestive of a relapse or second clinical episode since the baseline MRI is a reli- progression for 20 to 25 years.5,6 able indicator of developing CDMS and long-term dis- The recently published data from the more compa- ability. The Optic Neuritis Treatment Trial (ONTT),8 rable long-term study of CIS patients by Fisniku et al.6 national hospital study,6 and Barcelona study9 all pro- recruited for a baseline MRI scan between 1984 and vide evidence that having a positive baseline MRI scan 1987 show a much more favorable prognosis than significantly increases the risk of future conversion to demonstrated in the London, Ontario, and Lyon stud- CDMS compared with having a normal baseline MRI ies. Twenty years after the diagnosis of CIS, of the scan. However, even having a baseline MRI scan with a patients with abnormal baseline MRI studies, 18% had large number of T2 lesions does not nearly guarantee not developed CDMS, and an additional 39% had conversion to CDMS even after many years of follow- EDSS scores of 3 or less. Therefore, at least 57% (23% up in any of these cohorts. of the cohort were lost to long-term follow-up) of the In addition, and perhaps more importantly, neither CIS patients with abnormal baseline MRI studies had a the 15-year data from the ONTT8 nor the recently good or an excellent outcome over 20 years. This was reported 20-year data from the national hospital study6 International Journal of MS Care 104 Controversy provide evidence to support the belief that baseline mented that even CIS patients with a positive base- MRI lesion load translates into that all-important reli- line MRI scan have a reasonably good chance, about able predictor of long-term disability. The ONTT 20%, of not developing further clinical symptoms of found no correlation between the number of T2 lesions MS over a 20-year period,6 and pre-MRI natural his- at baseline and disability at 15 years. Fisniku and col- tory suggests that 1 in 5 will have no further symp- leagues6 found that 18% of patients with 10 or more toms after 25 years.5 Therefore, if one started IFNβ T2 lesions at baseline had not developed CDMS at 20 or glatiramer acetate in a patient with CIS, when years and that another 35% had minimal disability would one consider stopping treatment? Would the (EDSS ≤3). Therefore, more than half of the patients CIS patient continue on the drug for 20 years if he or in their cohort with highly active baseline scans had a she remained relapse-free because of the perceived ben- reassuringly favorable outcome even at 20 years after efit to the patient or the physician? At a drug cost their first relapse. alone (based on UK prices) of approximately £120,000 Therefore, patients with CIS appear to have both a to £180,000 (approximately $192,000 to $288,000) low ARR and a significantly better long-term prognosis for 20 years of administration, any error in this deci- than those with clinically definite RRMS even when sion would be a costly one, not to mention the 1040 to their baseline scans are highly abnormal. It also seems 7300 injections the patient would have to endure, with clear from the natural history evidence that those diag- the accompanying "medicalization." nosed with CDMS as defined by Poser's criteria have a The BENEFIT study states that the "patient num- significantly worse prognosis in terms of both relapse ber needed to be treated in order to prevent one case of rates and long-term disability. CDMS (ie, one relapse) within the study period of 2 years is estimated to be 5.9."3 This equates to approxi- Costs for Patients and Taxpayers mately 12 years of treatment (624 to 4380 injections) at Another issue related to treatment timing is the cost a drug cost alone of approximately £72,000 to £90,000 involved for both patients and taxpayers. Those of us ($115,000 to $144,000) to stop one relapse in 12 who work within the UK National Health Service are patients over a 2-year period. If one assumes that the made acutely aware of the cost/benefit ratio of poten- average length of disability caused by a relapse is 2 tial treatments. The Association of British Neurologists months, this equates to a drug cost of between £432,000 released revised guidelines in 2007 regarding the sug- and £576,000 (approximately $691,000 to $921,000) gested use of disease-modifying treatments for MS cli- per year of patient disability benefit. Given that many of nicians in the UK. These included approval for treating these relapses will be mild and often do not affect activi- patients with CIS who met stipulated MRI criteria. ties of daily living and there are additional costs in terms However, perhaps following controversy, these guide- of physician consultations, blood tests, and so on, the lines were subsequently withdrawn and are awaiting real cost will be substantially higher still. In addition to further revision.10 Importantly, the decision whether to this financial cost, and perhaps more importantly, the treat CIS patients has yet to be addressed by our Nation- other 11 patients will experience no benefit, but they al Institute for Clinical Excellence (NICE). Perhaps as will often experience unpleasant side effects and the a result, beginning IFNβ or glatiramer acetate treat- accompanying "medicalization" that starting treatment ment in CIS patients has not been widely accepted in with IFNβ or glatiramer acetate entails. the UK. Additionally, and extremely importantly, there is the Each of the CIS treatment trials reported that over a possibility of misdiagnosis. In my experience, the diag- 2- to 3-year period on treatment approximately 15% of nosis of MS tends to become easier and more secure patients avoided a relapse, as compared with placebo. with increasing duration of the illness. The differential The ETOMS, CHAMPS, BENEFIT, and PRECISE diagnosis of CIS is wide, and no matter how experi- data therefore suggest that approximately 85% of enced or talented the physician, it is unavoidable for patients starting IFNβ or glatiramer acetate will experi- some patients to be misdiagnosed and thus potentially ence no benefit. In addition, 50% to 55% of these mistreated. If one includes the CIS patients who will patients would not have had a relapse whether treated not convert to CDMS, the potential for misdiagnosis or not. Indeed, as already highlighted, it is well docu- and mistreatment is very large—approximately 50% at International Journal of MS Care 105 Controversy 2 years and 20% at 20 years. These figures are substan- mencing these agents in CIS patients we may inadver- tially higher than the 15% of patients whose second tently do more harm than good. Hence, until we have relapse is delayed. a reliable prognostic indicator and a treatment with proven long-term efficacy, is it not best to wait until at Conclusion Many patients might argue, rightly, that the finan- least that second clinical relapse to avoid potentially cial cost is immaterial if treatment will improve their unnecessary, costly, and harmful (in terms of side effects quality of life and reduce their disability over the 40 to and medicalization) treatment, since this is clearly a bet- 50 years of their illness. In addition, many MS special- ter predictor than a positive MRI study, or any other ists have suggested that treating patients early may test, of possible future deterioration? modify their disease in the long term. Yet one could Financial Disclosures: Dr. Cottrell has received unrestricted argue that the beta-interferons and glatiramer acetate research grants from Merck Serono, Teva Neuroscience, Biogen Idec, even in the responding CIS patients do not prevent the and Bayer-Schering (in total, less than £250,000, or approximately process of MS, except simply by means of "definitions" $400,000), as well as direct honoraria for lectures and participation over a short period of time, which may not be a clini- in advisory board meetings from Bayer-Schering, Biogen Idec, cally meaningful way to think of therapy for a chronic, Novartis, and Merck Serono (totaling less than £10,000, or approxi- mately $16,000). relapsing disease. Indeed, each of the CIS treatment trials includes References patients with highly active baseline MRI scans (median 1. Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treat- T2 lesion load, between 5 and 24). This suggests that ment on conversion to definite multiple sclerosis: a randomised study. Lancet. 2001;357:1576–1582. the process of central nervous system demyelination 2. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta- has been present for some considerable time prior to 1a therapy initiated during a first demyelinating event in multiple their clinical presentation. Therefore, the argument sclerosis. N Engl J Med. 2000;343:898–904. 3. Kappos L, Polman CH, Freedman MS, et al. Treatment with interfer- that these trials represent "early treatment" appears on beta-1b delays conversion to clinically definite and McDonald flawed, and so to propose that we must avoid a relative- MS in patients with clinically isolated syndromes. Neurology. ly arbitrary delay in one relapse during a 40- to 50-year 2006;67:1242–1249. 4. Ebers GC, Heigenhauser L, Daumer M, Lederer C, Noseworthy JH. illness by introducing a treatment that appears to have Disability as an outcome in MS clinical trials. Neurology. 2008; no impact on disability is perhaps unsustainable. 71(9):624–631. Intuitively, I agree that there is an attractive hypo- 5. Eriksson M, Andersen O, Runmarker B. Long-term follow up of patients with clinically isolated syndromes, relapsing-remitting and thetical link between early treatment and delay in long- secondary progressive multiple sclerosis. Mult Scler. 2003;9: term disability. However, in MS this presupposes that 260–274. the treatments in question are effective in preventing 6. Fisniku LK, Brex PA, Altmann DR, et al. Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple disability. Sadly, there is no convincing clinical or trial sclerosis. Brain. 2008;131;808–817. evidence yet to support early treatment on grounds of 7. Kremenchutzky M, Rice GP, Baskerville J, Wingerchuk DM, Ebers preventing long-term disability or, crucially, delaying GC. The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the dis- the onset of progressive disease. ETOMS reported inter- ease. Brain. 2006;129:584–594. feron to have no significant effect on the accumulation 8. The Optic Neuritis Study Group. Multiple sclerosis risk after optic of disability; likewise, the 10-year open-label extension neuritis: final optic neuritis treatment trial follow-up. Arch Neurol. 2008;65(6):727–732. study of the CHAMPS cohort showed a lack of effect 9. Tintoré M, Rovira A, Río J, et al. Baseline MRI predicts future attacks on disability as measured by the EDSS or MSFC. and disability in clinically isolated syndromes. Neurology. 2006; As an MS physician, I would like nothing better for 67:968–972. 10. Scolding N, Wilkins A, Cottrell D. New guidelines for MS treat- my patients than an early, safe treatment modality with ment—no cause for celebration. Adv Clin Neurosci Rehabil. 2007; long-term efficacy. My fear, however, is that by com- 7:17–18. International Journal of MS Care 106


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Posts tagged: Nicolas Garcia-Godinez
A Grant County teen faces five felony charges, including attempted murder, after police saw he fired shots at a Washington Department of Fish and Wildlife police captain Saturday.
Jose J. Garcia-Meraze (left) is charged with unlawful imprisonment for the incident at Crab Creek near Beverly after "he basically disarmed a Fish and Wildlife agent at gunpoint," said John Turley, Grant County undersheriff.
The 18-year-old also is charged with second-degree assault, attempting to elude and alien in possession of a firearm, Turley said. His father, 60-year-old Nicolas Garcia-Godinez (right), is jailed on a second-degree assault charge for allegedly pulling a knife on another officer.
U.S. Immigration and Customs Enforcement has placed holds on both men.
Garcia-Meraze, was fishing without a license at Crab Creek when he pulled a gun on an approaching officer and fled in a car, police reports said. The teen allegedly turn around and drove toward the officer's marked police vehicle, firing shots and penetrating the driver's side door with one round. An officer returned fire after the teen attempted to shoot at him a second time, police said.
Garcia-Meraze was arrested after his car stalled on state Route 28 near Ephrata, police said. Both men are in Grant County Jail.

subset: commoncrawl


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Altman, HowardTribune Staff
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VA retaliation lawsuits near final phase
For Kendra DiMaria, a former law enforcement officer with the Bay Pines VA Healthcare System police department, her problems with management began in the summer of 2009 when a supervisor began making sexual innuendos, ac...
'Spirited' exhibit opens at Tampa Bay History Center
It was an era that changed American behavior in ways no one could have anticipated.
Betty King Culbreath-Gibbons dies at age 92
Betty King Culbreath-Gibbons, who was married to two of Tampa's most influential men, lived a life of public service.
Altman: Sharing intel can backfire for U.S.
One of the biggest security challenges the U.S. faces is how to share intelligence in a world where it's been at war at one point with some of its closest friends, you never know who tomorrow's enemy will b...
Army Gen. Votel takes over command of Socom
Nelson will seek authority for use of force in Syria
Sen. Bill Nelson, just back from a trip that took him to Turkey and Ukraine, says he will raise the issue of the use of U.S. force in Syria against the Sunni insurgent group Islamic State when the Senate returns from vac...
McRaven made troops' health his top priority
Military involvement called into question in court case
The 35-year-old man from Miami headed to Clearwater in January, according to court documents, thinking he was going to meet up with Emily Millerson, who placed a personal ad on Craigslist soliciting opinions on which bra...
Hostage rescues fraught with danger, ex-commandos say
Tampa woman to be honored at White House ceremony
A Tampa woman, whose husband serves at MacDill Air Force Base, is one of 11 people who will be honored by the White House for "doing extraordinary work across the country as leaders in entrepreneurship," ac...
Services in St. Pete for decorated Marine who stirred outrage
TAMPA — The body of Marine Cpl. Rob Richards, a St. Petersburg native and war hero who touched off international outrage through a video showing him and three others urinating on dead Taliban fighters, is coming h...
Tactics against journalists in Ferguson threaten rights of all
In Ferguson, Missouri, heavily armed police in heavily armored vehicles were responding to protests over the police shooting of an unarmed black teen by firing off tear gas and dragging reporters out of McDonald's...
Congress seeks more information on VA deaths
TAMPA — Veterans Affairs Secretary Robert A. McDonald has ordered a review of the VA's national consult database, an independent review of the consultation process and clarification by a top VA official of ...
MacDill hurricane hunters to get $35 million overhaul
"Miss Piggy" is getting new wings.
Tampa's Iraq veterans have big hopes for Kurds
Florida group meeting on growth strategies for defense industry
In 2012, military spending in the three-county Tampa region accounted for nearly $14 billion in economic output, 141,000 jobs and represented about 7 percent of the economies of Hillsborough, Pinellas and Polk counties, ...
Sen. Nelson headed to Ukraine; says U.S. should arm Kiev government
Sen. Bill Nelson, gearing up for a trip this week that will take him to Ukraine, the Baltic states and Turkey, departed from the Obama administration's more measured approach and called for providing lethal arms t...
Center will help former MacDill service members stay in Tampa
Every year about 1,200 to 1,500 service members from MacDill Air Force Base leave the service.
Tulley takes MacDill helm as Iraq airstrikes ordered
MacDill's Col. DeThomas discusses his command as it reaches end
A week before assuming command of the 6th Air Mobility Wing two years ago, Col. Scott DeThomas got a taste of what he was in for as the officer in charge of MacDill Air Force Base, a 5,700-acre facility with more than $2...
Slain general explained mission in letter
Surveillance camera removed from VA office in St. Petersburg
A surveillance camera set up outside of the office of the union representing workers at the Veterans Benefits Administration St. Petersburg Regional Office has been removed, union officials say.
Bay Pines VA meetings set to explain care improvements
The director of the Bay Pines VA Healthcare System will hold a new series of meetings with veterans service organizations, Congressional district office staff and other "stakeholders" to explain "eff...
Soldier forced to stay in uniform or lose benefits
TAMPA — After nearly 20 years in uniform, Army Lt. Col. T.G. Taylor wants to retire.
Mold forces relocation of Haley hospital patients
TAMPA — About a half dozen patients in the James A. Haley Veterans' Hospital Spinal Cord Injury Center had to be moved and a hallway sealed off after mold was discovered in an area near the patient care sec...
Lakeland fighter-jet company seeks state funds for expansion
McRaven named only finalist for University of Texas chancellor
If everything goes as planned, Adm. William McRaven, the outgoing commander of U.S. Special Operations Command, will be setting aside his gold Navy SEAL trident next year for the orange longhorn emblem of the University ...
Family seeks justice in shooting of pregnant woman
A day after her sister died from a gunshot wound to the head, Kayleigh Bryan says her family is "destroyed" and wants charges brought against the man deputies say fired the fatal shot.
Socom's McRaven a contender for University of Texas chancellor post
Watch out University of Texas students.
POW recalls time in Stalag 7a and his run to freedom
On Nov. 16, 1944, Albert Torchia, an Army private from Verona, Pennsylvania, was holed up with his squad from the 104th Division in a house in the German town of Stolberg.
Automated car takes test drive on Selmon Expressway
Following behind a small phalanx of Audis traveling down an otherwise empty stretch of the Selmon Expressway's elevated lanes, Kaushik Raghu takes his hands off the steering wheel of the gray 2012 Audi A7 with a v...
Pregnant woman, child die in shooting
A pregnant Citrus County woman and the child she was carrying have died after the woman was shot in the head in what Hernando deputies are calling an accident at a friend's home in Brooksville.
Woman escapes, dog dies in Riverview barn fire
A Riverview woman escaped a fire in the pole barn where she was sleeping, but her small dog perished, Hillsborough County Fire Rescue officials say.
Socom change of command set for late August
Army Gen. Joseph Votel will officially take the helm of U.S. Special Operations Command during a change of command ceremony Aug. 28, at 2 p.m. at the Tampa Convention Center.
Senate approves Votel as Socom commander
Joseph Votel, newly minted Army four-star general, will become the 10th commander of U.S. Special Operations Command.
Gen. Austin expresses concern about Iraq security
After a 24-hour visit to Iraq where he met with senior U.S. officials and Iraqi leaders across the political spectrum, the commander of U.S. Central Command said he is "very concerned about the current security si...
St. Pete VA center camera riles union
A week after a former employee and union official testified before congress about problems at the Veterans Benefits Administration St. Petersburg Regional Office, management installed a surveillance camera outside the of...
VA committee demands records from St. Pete
MacDill may get $32 million in upgrades for new jets
MacDill Air Force Base will likely receive about $32 million in upgrades to accommodate eight new KC-135 refueling jets scheduled to arrive here over the next few years, according to U.S. Rep. Kathy Castor.
MacDill among best bases in rankings by Air Force Times
MacDill Air Force Base, the only military installation in the world home to two U.S. combatant commands, may be loved in the Tampa area, but it was tied for sixth best in
TAMPA — The downing of Malaysia Airlines Flight MH17 over eastern Ukraine might have happened because Russian-backed separatists thought the passenger plane was a military aircraft, a colonel in the Ukraine army s...
Rebels might have thought jet was military, Ukrainian colonel at MacDill says
TAMPA — The downing of Malaysia Airlines Flight MH17 over eastern Ukraine might have happened because Russian-backed separatists thought the passenger plane was a military aircraft, a colonel in the Ukraine army s...
DigitalGlobe training satellites on Ukraine
DigitalGlobe, a satellite imagery company with an office in Tampa, is training its eyes in the sky on Ukraine as the result of a passenger plane Ukrainian authorities say was shot down with nearly 300 passengers and crew...
Friends, family say farewell to St. Petersburg veteran
As thunder boomed, lightning crackled and an honor guard fired volleys into the air, family and friends gathered around a kiosk at the Bay Pines National Cemetery to bid a final farewell to a beloved soldier.
Director tops salary list at VA St. Pete Regional Office
The highest paid employee of the Veteran Benefits Administration's St. Petersburg Regional Office — the nation's busiest VA claims processing center — has a salary of $152,536, according to in...
Testimony: VA criticism led to St. Pete layoff
VA salaries, bonuses plentiful in Tampa area
New leader takes command of MacDill refueling wing Sunday
Command of the 927th Air Refueling Wing at MacDill Air Force Base will be changing hands Sunday at 9 a.m.
Lawyers needed to help veterans cut red tape
St. Petersburg-based lawyer Matt Weidner devotes a good deal of time helping veterans navigate the legal system.


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Rugby League
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Josh Charnley
World Club Challenge: Wigan coach Shaun Wane confident on fitness of England trio
Saturday 8th February 13:39
Wigan coach Shaun Wane remains confident Sean O'Loughlin, Michael McIlorum and Josh Charnley will be available for their World Club Challenge match against the Sydney Roosters.
Rugby League World Cup: Josh Charnley relishing Saturday's semi-final battle
Tuesday 19th November 13:41
England winger Josh Charnley cannot wait to sink his teeth into New Zealand in Saturday's mouth-watering Rugby League World Cup semi-final clash.
Super League: Shaun Wane says comments by Denis Betts fired up Wigan Warriors
Saturday 23rd March 21:19
Wigan coach Shaun Wane says his players reacted to comments made by Widnes boss Denis Betts as they prepared for their 62-4 victory at the DW Stadium.
England international trio sign new contracts with Wigan Warriors
Tuesday 13th November 14:53
England stars Josh Charnley, Sean O'Loughlin and Michael McIlorum have signed new long-term contracts with Wigan Warriors.
Wigan wait over Charnley
Tuesday 10th July 16:08
Wigan coach Shaun Wane doesn't expect to know until the end of the week if winger Josh Charnley will be fit to face Leeds on Saturday.
Charnley could miss semi-final
Friday 6th July 09:04
Josh Charnley is doubtful for Wigan Warriors' Carnegie Challenge Cup semi-final against Leeds Rhinos on July 14 at Huddersfield.
Charnley to put the boot in
Monday 21st May 10:36
Wigan's Josh Charnley is aiming to get things right in front of goal after missing four conversions in the win over Huddersfield.
Knights put French to sword
Saturday 15th October 17:35
Richie Myler responded to his England Four Nations snub with an impressive display in the Knights' 38-18 win over France.
Wigan quiet over Thomas link
Thursday 1st September 11:12
Wigan are silent over rumours linking them with a move for three-quarter Gareth Thomas who will leave Crusaders at the end of the season.
Injury checks for Wigan pair
Sunday 28th August 13:34
Wigan pair Josh Charnley and Lee Mossop will undergo scans this week after playing through the pain barrier at Wembley.
Brotherly love boosts Wigan
Friday 4th February 13:28
Siblings Joel and Sam Tomkins are two of six players who have signed new contracts with reigning champions Wigan.
Maguire - Charnley is ready
Thursday 19th August 12:25
Michael Maguire would have no problems playing Wigan's Josh Charnley against Hull KR after his recall from a loan at the Robins.
Rovers v Rhinos: Teams
Thursday 8th July 08:51
Hull KR full-back Shaun Briscoe returns from injury for the visit of Leeds Rhinos to New Craven Park on Friday.
Super League: Leeds Rhinos Challenge Cup win caps a great era
In years to come when they look back on the great teams in the history of rugby league they will talk of the Wigan dominance of the late eighties to the mid-nineties, the 1982 and 1986 Kangaroo tourists and others such as Huddersfield's 'Team of all talents' around 100 years ago.
Good Week/Bad Week: We take a look at the winners and losers from the last seven days
So much can change in a week of sporting action and, sure enough, there have been plenty of highs and lows over the past seven days.
Experts & Blogs
Read the thoughts and opinions of Stevo with skysports.com


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For Fadden, Time Is NowSubmitted by timothy on August 30, 2008 - 13:18
For Mitch Fadden, September will be the month that decides where he spends the next year. As the Lethbridge training camp begins, Tampa's 2007 4th round pick is still without a pro contract from the Lightning. After attending the Bolt's Prospect Camp in Victoria, BC last month, the Lightning still want to see more of Fadden before making a decision on where he spends the 2008-09 season.
In talking with the Lethbridge Herald, the WHL's sixth leading scorer was upbeat about the start of the Hurricane's camp, "It's business as usual, everyone is excited to get back on the ice and we're ready to start the season.â€
Len Barrie: Potential Lightning Owner, Etc..Submitted by chad on May 22, 2008 - 10:51
The golf cart had a dashboard like a Lexus, headlamps and a top speed of about 45 clicks, which was all right because it also had seatbelts. Best of all, it was equipped with satellite radio that softly filled the spring air with new rock.
Al Czervik would have been proud.
You remember Al? He was the plaid-panted, brash but likable real-estate tycoon in Caddyshack played by Rodney Dangerfield, whose golf bag had a built-in stereo that blasted Journey all over Bushwood Country Club.
For the rest of the story, which includes potential titles for Barrie and rumored partner Oren Koules, as well as examples of Barrie's business style, Click Here (Victoria Times-Colonist).
Lightning Wins NHL Draft LotterySubmitted by pete on April 7, 2008 - 19:26
[acidfree:3279 size=400 align=right]
The Tampa Bay Lightning have won the draft lottery for the 2008 NHL Entry Draft and secured the #1 pick in the draft.
Dave Andreychuk, who sat in as the Lightning's representative for the draft drawing, has the magic mojo.
Steven Stamkos is a Bolt.
Can you say, "skill?"
Welcome to Tampa Bay, young man.
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BoltProspects 2007-2008 Mid-Term Rankings ReportSubmitted by pete on March 4, 2008 - 02:18
This is a bit late (for a variety of pseudo-reasons), but at last the lengthy evaluation process is complete.
Today, Bolt Prospects is releasing its Mid-Term Rankings for the 2007-2008 season. Defenseman Mike Lundin has joined the graduated prospect list; therefore, he is no longer on the prospect rankings list. Mario Scalzo, acquired earlier in the season from the Dallas Stars organization, makes his debut on the rankings list.
Norfolk Signs Quick to ATOSubmitted by timothy on February 9, 2008 - 01:29
Norfolk Admirals (AHL) General Manager Claude Loiselle announced today that Norfolk has signed defenseman Kevin Quick to a 25-game Amateur Tryout Contract (ATO).
Quick, a 6-foot-0, 175-pound defenseman, had two goals and two assists in 21 games with the University of Michigan Wolverines this season prior to joining the Admirals. The 19-year-old was drafted by the Tampa Bay Lightning in the third round (78th overall) of the 2006 NHL Entry Draft out of The Salisbury School in Connecticut.
Quick was dismissed by Michigan last week for violating team rules. The Buffalo News has released a report on the incident.
A comprehensive overview of Quick's present situation, with quotes from Loiselle and Quick, was published out of Norfolk can can be found here. For more details of the signing, see the St. Petersburg Times.
- 8 comments
- 2233 reads


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The following editorial appeared recently in The Seattle Times:
Mitt Romney and President Obama need to talk about spending and debt, and as adults. They have to be believable, and their arithmetic has to work.
Here is the problem. For four years the federal government has run a deficit of at least $1.3 trillion. The federal debt is now $15.7 trillion, one-third of it borrowed in Obama's time.
Stabilizing the debt should be one of the central issues of the 2012 campaign.
Obama has been chatting up the Buffett Rule, under which million-dollar earners would pay a minimum tax. There is a fairness case for this. The problem is that there are too few rich people who are paying at lower rates than Warren Buffett's secretary. As a solution to the problem of spending and debt, the Buffett Rule is a mere footnote.
Obama has better material if he wants it. He appointed the National Commission on Fiscal Responsibility and Reform. It set a goal of reducing federal spending to 21 percent of gross domestic product by 2035, down from 23.8 percent.
The commission would do this by reforming future pensions, increasing the retirement age and shaving the Social Security benefit formula. It would increase revenues by broadening the Social Security tax base, treating dividends and capital gains as ordinary income and having all income-tax payers take the standard deduction on Form 1040.
You can see the commission's proposal on the Internet. We don't agree with all of it, but it is serious. And you don't hear much about it from Obama.
On his Web page, Romney wants to lower federal spending to 20 percent of GDP by 2016. This would be a huge change. But how to do it? Romney would cut subsidies to Amtrak, artists, public TV and legal services.
Those, however, are small items. He would increase military spending, which is a big item. Only one of Romney's proposals, turning Medicaid into block grants, would take a big bite out of a big current program, and it is not enough.
Romney also needs to increase revenues to 20 percent of GDP, and he offers little to nothing about that.
Regarding spending and debt, both of these candidates fail the arithmetic test. One of them needs to pass it.
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The rest of the interview was just as verbally confusing. Stephanopoulos was able to extract a few pieces of information from Rodman before their time was up, though: Kim Jong-un doesn't want war, both Kim Jong-un and Barack Obama love basketball and Kim Jong-un wants President Obama to call him. Here's how the interview ended:
STEPHANOPOULOS: Next time you go back you should bring this report from Human Rights Watch with you and maybe ask him questions about that as well. You might learn a lot more and it might press him as well. But thank you for coming on this morning and sharing your impressions.
RODMAN: But either way, either way, guess what though, guess what, thank you for the report. Guess what, guess what, don't hate me, don't hate me, guess what, don't hate me, guess what, don't hate me.
Rodman inserted himself into geopolitics at a time when North Korea's usual chest-thumping has quickly become more vocal than usual.
"North Korea on Friday responded to tougher sanctions from the U.N. Security Council with another barrage of vitriol, repeating a vow to ditch all nonaggression pacts with the South," reported CNN. "A day after the isolated regime in Pyongyang had threatened a possible 'pre-emptive nuclear attack,' something analysts say they think is unlikely, its official news agency reeled off a number of agreements with South Korea that it said would no longer apply."
North Korea hopefully, probably won't restart the Korean War any time soon. But if I were President Obama, I'd keep Rodman's phone number on speed dial just in case. At first glance, Rodman being one of the only Americans Kim Jong-un has ever met in person seems strange. But, if you really think about it, it sort of makes sense. North Korea has been referred to as the "hermit kingdom" for its heavy-handed isolationism. To promote his 1996 autobiography "Bad As I Wanna Be," Rodman famously wore a wedding dress and said he was marrying himself. Rodman and North Korea are two singularly self-contained entities. Of course they would hang out. Rodman gets to be crazy in public for the same reason North Korea does: they both have the goods to back it up. Rodman, for all his insanity, is still considered one of the best rebounding forwards in the history of professional basketball. North Korea may still be caught in the Stone Age culturally, but they do have nuclear weapons. You can dismiss Dennis Rodman. You can roll your eyes at North Korea. But you do both at your own peril.
Rob Burgess, Tribune night editor, may be reached by calling 765-454-8577, via email at email@example.com or on Twitter at www.twitter.com/robaburg.


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Very comfortable, clean B&B that is nicely decorated located not far from city centre. Generous selection of food (cereal, milk, juice, jam, yoghurt) that is available all day was great. The owner was very friendly. The room is a little dark and can get quite cold but electric blanket was provided that that kept us warm.
- Reservation Options:
- TripAdvisor is proud to partner with Agoda, Booking.com and BookingOdigeoWL so you can book your Edinburgh Gallery Bed and Breakfast reservations with confidence. We help millions of travelers each month to find the perfect hotel for both vacation and business trips, always with the best discounts and special offers.
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- Edinburgh Gallery Bed And Breakfast Hobart, Tasmania


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Shifting to other crops after cutting down palms
Farmers in Wayanad are increasingly shifting to other crops after cutting down areca nut palms. Diseases affecting the palms, uncertainty in price of the produce, and dearth of incentives have forced their hand.
Areca nut production in the district had fallen sharply in the past five years due to various crop diseases, especially the yellow leaf disease.
According to data from the Agriculture Department, 80 per cent of the 12,730 hectares under areca nut cultivation had been affected by the yellow leaf disease.
"Nearly 25 per cent of the area under areca nut is under crops such as rice, banana, and oil palm now," Alex C. Mathew, Deputy Director, Agriculture Department, said.
"I have been cultivating areca nut on one acre for the past 15 years and used to get an average of 20 quintals of nut every year for the first ten years," Jose of Kandammalil, a small-scale farmer, told The Hindu.
He had now shifted to banana cultivation after cutting down areca nut palms on his land. He said production declined sharply after the spread of the yellow leaf disease and he got only two quintals of nut last year. Similar is the experience of the majority of farmers in the district.
Diseases such as bud rot and nut rot (Mahali) had ravaged the crop in the past five years but the government had not taken any step to compensate the farmers, sources said.
The huge fluctuation in price of the produce in the local market during the harvest season also deterred the farmers from going ahead with areca nut cultivation.
The price of tender areca nut was Rs.76 a kg a few months ago but the spot price in the local market on Monday was Rs.66 a kg, the sources said.
The better price for paddy after the market intervention of the government and the introduction of crops such as oil palm had also encouraged the farmers to bid adieu to areca nut cultivation.
Rumours of a Central government move to ban areca nut products had also hastened the decision of the farmers to shift to other crops.
Keywords: Areca farmers in Kerala, Wayanad farmers, areca nut prices


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La Bande de Plaquemine Brulee and the Midnight Ramblers will perform Saturday, April 5, at the historic Liberty Theater in downtown Eunice.
The weekly "Rendez-vous des Cajuns" music show will broadcast the show. Rendez-vous des Cajuns is broadcast on KRVS 88.7 FM.
Best described as the "Cajun Grand Old Opry" the family-friendly show features an emcee who hosts the show in Cajun French and a dance floor where people can dance to the music of Cajun bands performing live in the restored 1924 vaudeville house.
Tickets go on sale every Saturday at 4 p.m. at the ticket window of the Liberty Theater. Tickets are $5 and general admission seating.
La Bande de Plaquemine Brulee take the stage first followed by the Midnight Ramblers.
The show starts at 6 p.m.
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Rabbi Ari Kahn received his rabbinic ordination from Yeshiva University's Rabbi Isaac Elchanan Theological Seminary where he studied with Rabbi Yosef Dov Soloveitchik. He graduated Yeshiva University with a BA in psychology and an MS degree in Talmud. He is Director of Foreign Student Programs at Bar-Ilan University in Israel, where he also is a senior lecturer in Jewish studies. He is a renowned speaker, and has lectured worldwide. Having authored hundreds of articles on the weekly parasha and holidays with a readership in the thousands, Rabbi Kahn is also the author of Explorations, an in-depth analysis of the weekly Torah reading, and Emanations, an in-depth analysis of the Jewish holidays. A new series - "Echoes of Eden" is currently in progress. This is a projected 5 volume set to be published by the OU and Gefen Publishing. The first four volumes are in print and the fifth is in production.
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PostSharp Technologies, makers of advanced software development tools, today announced the availability of the PostSharp 3 RTM, a comprehensive design pattern automation product for the Microsoft .NET developer platform.
The RTM marks an evolutionary step forward for the company's flagship product, offering deeper Visual Studio integration with content-sensitive smart tags and a wizard-like user interface that enables developers to automatically inject ready-made implementations of common design patterns into their applications to reduce complexity, simplify architecture and add new functionality.
Developers can select from a growing library of ready-made design pattern implementations, including:
• INotifyPropertyChanged and Code Contracts;
• Logging for Log4Net, NLog, System.Diagnostics, and Enterprise Library;
• Multithreading (including thread models and thread dispatching); and
• Design rules enforcement
Gael Fraiteur, PostSharp Technologies CEO, described how years of good customer relations led to the innovation:
"During the last 8 years, we successfully positioned PostSharp as the leading framework for aspect-oriented programming on the Microsoft .NET developer platform, and told developers they could build whatever they wanted with it. Over time however, we became increasingly aware that the vast majority of our customers were all re-implementing the same patterns."
Having noticed the trend, the company began to steadily build a library of the most common .NET application design patterns and, with PostSharp 3, the ready-made libraries are now built-in to the product itself, enabling customers to apply them to their code bases in minutes instead of having to build them from scratch.


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The Westin Mission Hills Golf Resort & Spa
Trattamento per il viso
Indulge yourself. Epicuren products energize your skin with deep cleansing, an enzyme exfoliant, layers of nourishing masks, and collagen concentrates. You'll enjoy it even more under a blissful massage of your face, scalp, shoulders, and hands.
- Tariffe: 80 minutes/$190


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|Total (w/tax)
|Total (w/tax)
Book Description:
The ability to read law well is an indispensable skill that can make or break the academic career of any aspiring lawyer. Fortunately, the ability to read law well (quickly and accurately) is a skill that can be acquired through knowledge and practice. First published in 2005, Reading Like a Lawyer has become a staple on many law school reading lists for prospective and admitted students. The second edition includes the same critical reasoning and reading strategies, accompanied by hands-on practice exercises, that made the first edition such a success. It adds a valuable new chapter on a growing challenge for this generation of legal readers: how to read material that is presented on a screen with maximum efficiency and effectiveness.
Tags: Reference,


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The Genius Of Outkast
April 26 marks the 20th anniversary of OutKast releasing their classic debut Southernplayalisticadillacmuzik. The album made a clear statement that when it came to competing on a lyrical and concept level, the South could stand toe-to-toe with the East and West Coasts, which were dominating at the time.
With that seminal release, Big Boi and André 3000 sparked the creative juices throughout the South and the region came to dominate the hip hop game. BET.com caught up with Big K.R.I.T., a recent spawn of the Dirty, as he weighed in on the importance of this album and Kast's legacy in hip hop. A true student of OutKast, Big K.R.I.T. offers his thoughts on 20 classic songs from Dre and Big Boi. -Michael Harris @IceBlueVA
"The thing about Southernplayalisticadillacmuzik, I was young at the time when it came out in 1994. I remember the single 'Player's Ball' and Outkast made it cool to be southern, and Dre standing up for The South at The Source Awards when he said, 'The South got something to say'," K.R.I.T. kicks off.
"The album was phenomenal and an influence on the kind of music I create, and Organized Noize's production was an inspiration to me. They made it to where the South was respected and could hold our own in a lyrical fashion and songwriting fashion," he continued.
"And taking it farther than that, they put themselves in a position where it's not really a genre you can put Outkast in. They created their own lane and made it OK to be yourself and it just wasn't this old extra elaborate gangsta type music," he said.
"It definitely opened up a different platform and doorway as far as creativity was concerned, and hip hop in general and just me being a southern artist, why not sing on a whole record? Why not do a song like 'Liberation; or get Big Rube to do a poem on your record? So a lot of things they did was groundbreaking, and what a lot of people weren't ready to do or too scared to do in the beginning."
(Photos from left: Bennett Raglin/BET/Getty Images for BET, Frazer Harrison/Getty Images)
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Would you buy this car?
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Drives: on the wrong side of the Ocean
Join Date: Jul 2008
Location: New Jersey, USA
Posts: 1,111
iTrader: (
Originally Posted by
You guys dont like buying used cars? WHY? Let me hear...cuz you dont know how it was broken in?
You're all just trying to make yourself feel better since you have already lost $20k by buying new.
Nothing wrong with buying a used car, as long as you do all your hw.
Sometimes, its ok to buy a car thats been in minor accident too, most likely you end up saving even more. In OP's case, this car had way too much damage to even consider buying it...
Why are you so aggressive? Had a bad weekend? Nobody is trying to justify anything here and just know that I am not upset about my car having depreciated! I perfectly knew about this fact before I bought my (new) car, but since I am planning on keeping the car for a while and also wanted to order it exactly the way I wanted it, etc... but this not the important point we are discussing in this thread.
Anyhow, you have many good points and, to tell you the truth, my next daily driver will probably be a used car. So, in theory I agree with you that, if you do your homework, you could probably find a car that had been properly cared for by a car nut like me (or you???), which would be a great financial decision. But truth be told, I tried that when I was looking for a used e46 M3 but was unfortunately not successful... which led me to order my e92... I have not looked back ever since!!!
2008 M3 Coupé | 1995 M3 LTW | BMW CCA Instructor
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VP Automotive's technicians accomplish everything from oil changes and engine replacements to paintless dent repair and diagnostics. They work on all makes and models of cars, specializing in luxury and classic vehicles. At their collision center, certified paint and body repair professionals restore busted up vehicles to like-new condition after accidents or making Chuck Norris angry. For customers seeking a whole new look, the crew can airbrush on a new coat of paint or make customized modifications, such as beefing up fenders and adding spoilers. Additionally, they staff glass experts who repair and replace chipped windshields, or darken windows with high quality tinting films.
The highly trained technicians at Jiffy Lube tend to about 24 million customers each year with services such as the Jiffy Lube Signature Service Oil-Change package, which helps promote the longevity of each vehicle. Staffers acknowledge that oil plays a crucial role in maximizing the lifespan of each car—it cools the motor and helps prevent moving parts from deteriorating. More than 20,000 technicians—all of which have completed an extensive training program certified by the National Institute Automotive Service Excellence (ASE)—service vehicles at Jiffy Lube. In addition to performing oil changes, technicians offer preventative services such as air-filtration and electrical-system maintenance, among others. Jiffy Lube's quality pledge includes a commitment to transparency, which stipulates that they will inform car owners of any necessary services, complete a service only after it has been approved, and refuse to replace windshields with saran wrap.
Founded in 1983 with a combination of Alan Cox's mechanical know-how and Sherry Richardson's business savvy learned at Georgia State University, Alan Cox Automotive has grown to include a team of ASE-certified technicians ready to revamp cars from Honda, Acura, Kia, Hyundai, and more, with services that span both the performance and racing spectra. Today, Sherry's technicians keep roadsters in highway-ready condition with general maintenance services and soup up autos with DynoTune installations, engine modifications, and novelty hood ornaments. Technicians stay in work mode outside of the garage, from Marshall Winkeljohn earning car-show plaudits for restoring a 1979 Honda Accord LX two-door from the frame up, to Jeremy Bucy cranking gears under pressure as a pit-crew member for Black Dog Racing.
The ASE-certified technicians at Atlanta Undercar Specialists, including owner and Marine Corps veteran Wayne Rowedder, know the undercarriages of a huge variety of vehicles like the backs of their oil-streaked hands. Utilizing more than 20 years of experience in the field, the techs replace oil, align tires, and ensure drivetrain functionality in speedy appointments. They also make quick work of brake checks and coolant system repairs, and they evaluate axles and timing belts during maintenance visits. Their services are all geared toward keeping each four-wheeled family member running year round, with oil changes, tire rotations, and advanced diagnostic services available should the horses in the engine become unruly.


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Just in time for the first day of school, the House of Ink Tattoos and Piercings on Frayser Boulevard held its annual Backpack for Tats event.
The business offered free tattoos in exchange for $30 worth of school supplies.
The store's annual backpack for tats drive is doing its part to take some of the expense out of school supplies for families. The more people donated to the drive, the bigger the tattoo offered.
The school supply drive ran July 30 & 31st.
House of Ink will donate the school supplies to students of Coldwell / Guthrie Elementary School.
You can still donate event though the event if over.
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We've been bumping into Craig John Davidson a lot recently. He's been a busy guy! In these past few weeks..
Tag Archives: Live At Captain Toms
Covers on the Couch at iiMusic with Craig John Davidson Our latest performer for Covers on the Couch is Craig..
See below for a list of Tickets available from our Aberdeen Store in the Academy Centre: Saturday 28th June Fat..


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Evil Queen Forum Posts
Klaroline or Forwood?
*I meant i like Captain Swan scenes..
Klaroline or Forwood?
Golden Swan was kind of intriguing in S1 but meh, I do not see any love there. Just manipulations for gain. But that was just a remote possibility that would never happen, not a ship.Dude i was kidding...he is her son's grandfather.GROSS.like ewwww to double infinity,,,,,Idk why everyone HAS to ship everything...I like Captian Hook scenes but i don't want them to hook up...Idk i just like Emma single tbh.
Klaroline or Forwood?
It has a nice slow, beautiful build up and its going to be epic.
In your head,I'd rahter Rumple and Emma hook up than Emma and Hook.ewww
I loved Kathryn for being the most atypical princess. Writers made her appear one way and then subverted expectations about the character
Meh,i liked her Ftl version a lil more but then i generally like everyone's ftl versions more(except cinderella)so thats no exception
Klaroline or Forwood?
you are such a hypocrite,
lol you distaste crackships and here you are crackshipping
Klaroline or Forwood?
Aurora is back?YAY.i love Aurora.adfghjkl;.just LOVE her..btw she does she appear in FTL or Storybrooke?
Well one princess I really dc for on there is cindy
Yeah me neither,in addition to making her seem like a ditzy blonde,they also made her a gold digger.My fave princess ruined forever...
For me, Out of heroines/princesses:
Snow >>>> Red >>> Belle > Kathryn > Mulan => Aurora >>>> Cinderella >>>> Ava For me too,excpet for Kathryn,idc for Kathryn,i loved how she slapped Snow tho LOL.
Klaroline or Forwood?
why can't those two idiots just snap her neck, take off her daylight ring, throw her into their vampire rehab dungeon until they figure out what to do with her....otherwise its just a walking and annoying problemSorry but no.This is basically the reason i wanted to beat the shit out of fagatore brothers today..acting all high and mighty when they've done the same shit a million times repeatedly.she'll turn on her humanity if and when she wants to,they are no ones to force her...and she has stated a million times that she doesn't want to be human anymore.so who in the fucking hell are they two force her.srsly Damon and Stefan don't love elena.they love thier week puppet with no agency at all.Elena should dump the both of them and tell them to go fuck themselves.
Klaroline or Forwood?
hopefully they go along SE lines with these two. that is if they are planning to carry it over.
You mean breaking and patching up a bajillion time.sorry.no.just NO
Klaroline or Forwood?
Is anyone reading any fanfiction right now?I cant find shit to read.
Klaroline or Forwood?
Meh,i want Elena to die first lol....Nina does do a good job playing Katherine,she should just stick to bitchy roles
if the KC kiss we get is a sweet thank-you with all good-bye feels I will not be happy. so much sexual tension with these two, they need atleast one awesome oneI'm pretty sure thats what we're gonna get like the DE kiss in 2x22.
Klaroline or Forwood?
I meant the guy who had a hand in killing Elijah's own brother....Basically the second part of your statement


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Treehouse Point in Issaquah, WA.
Ahhhhhh...visit the site and peak inside this treehouse...sophisticated! #Treehouse #Small Spaces
Beautiful Tree House Point: Washington offers you a beautiful natural setting in Issaquah Washington. This unique location is used for tourist lodging and also special events such as weddings and other ceremonies. Each tree house is handmade using the finest wood, glass and furniture. Many of the pieces inside each room such as the beds, dressers and tables are also handmade to match the room they furnish.


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Here are five prospects to watch who hail from either a Houston-area high school or play at a Texas college that could be early-round selections in the 2013.
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Looking for info on Carl and Noma Gray Hudelson. Noma was born 8/11/1886 in Dahlgren, Illinois to Noah and Amber McCoy Gray. Carl was a master mechanic, they lived in Sumter, South Carolina. Any info would be appreciated.
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I learned to make jam from my mom. We would cook together, using local produce and herbs from the garden. As I got older, and was living on my own, I started experimenting — and not all the results were a success! I failed so many times, with the jam not setting right or the jars not sealing. But the more I jammed, the easier it got, and I began developing my own recipes and techniques.
What's your favorite recipe in the book to make with produce available now?
That's hard, there's so much great fruit that's ripe right now! One of my personal favorites is a recipe I call "Umami Shiso Fine Plum Jam"— it's sugar-free and was inspired by a video you and I shot years ago of a pickled plum experiment, using the Japanese leaf herb shiso, which is used in the classic Japanese umeboshi plum. Both are available this time of year at the farmers market. (Ed: Ah yes, that video-attempt day. It actually inspired something??)
How much of the fruits, vegetables or herbs do you currently source from Brooklyn Grange Rooftop Farm for your flavors?
I wish I could source more fruit from them, but it takes a long time and lots of room to cultivate fruit orchards, not the perfect crop for urban rooftops! I do source all my herbs from them, and tomatoes and
peppers for pepper jelly and chutney.
What are some new flavors you're experimenting with that might be available soon?
I've been experimenting with a Bloody Mary Jam, a tomato jam with horseradish, peppercorns and vinegar. It's fun, and it tastes great with cheese and meat.
What's it like working in the kitchen of Eastern District as your jamming facility? Do you have a barter system of jam for cheese with them?
I do love cheese and they have an amazing selection, but no, we don't barter too much, we retain a nice amount of autonomy although we work in connected spaces — I do make a signature chutney for them that they use on a sandwich. I love renting my kitchen from them, we share a walk-in and warehouse space, and it's nice to have the company of neighboring tenants to banter with.
Do you have any plans to move your production or headquarters outside of Brooklyn?
As we grow into a larger facility in the coming year or so, I would love to be able to stay in Brooklyn. It's much more expensive to produce in the city, and much more difficult due to the burdensome bureaucracy of running a business here, high rent and limited space. But I love working and living in the city, and will remain here as long as I'm able.


text: Star Wars Xbox and Sherlock Season 2 DVD May Must Haves: Your Geek Girl Summer Essentials by Kelly Schwarze 5/01/12 10 Reactions 19 Shares Print 10 1 8 0 0 Before we start our Summer vacations, we'll be spending a few more days inside: perfecting our digital painting technique with a new iPad accessory, catching up on the latest season of a new geek classic, and basking in the glory of the coolest gaming console this side of Tatooine. See what the GeekSugar team must have this May in the slideshow! Limited Edition Star Wars Xbox 360 Kinect Bundle ($450) What's Your Reaction? 0 0 0 0 0 0 Even if you already own an Xbox 360, this Star Wars Xbox 360 Kinect bundle, which comes with an R2-D2-styled console, C-3PO gold controller, white Stormtrooper Kinect sensor bar, and a copy of Kinect Star Wars, is the ultimate buy for any gaming or Star Wars fan. Did I mention that the console comes complete with R2 sound effects? 1 / 5 Reveal Audry iPad Purse ($108) What's Your Reaction? 0 0 0 0 0 0 Finding a stylish way to tote your tech is great, but when it's eco-friendly to boot? Well, it doesn't get much better than that. The Reveal Audry iPad Purse is both earth-conscious and cool with its recycled suede, satin, zippers, and vegan leather exterior and an abundance of pockets to store your cords, adapters, chargers, and other tech accessories. It's the everyday bag that you can also use for a hot night out on the town. 2 / 5 Sherlock Season Two What's Your Reaction? 0 0 0 0 0 0 The second season of Sherlock begins May 6 on Masterpiece PBS. Better yet, you'll also be able to purchase season two on DVD to rewatch again for clues on May 22. 3 / 5 Sensu Brush ($40) What's Your Reaction? 0 0 0 0 0 0 Artists and Draw Something fanatics alike will enjoy the Sensu brush, a two-in-one paintbrush and stylus ready to revolutionize your tablet "paintings." Use the brush to create digital artwork rich with textured brushstrokes, watercolor-esque style, and detailed shading. 4 / 5 Swansea Beach Radio ($40) What's Your Reaction? 0 0 0 0 0 0 Get pool- and sand-ready in retro fashion with the Swansea Beach Radio. The ingenious design lets you tuck an iPod or iPhone inside the water-resistant plastic interior of the retro-styled speaker case, so you're not fretting about the elements interfering with your tunes. 6 / 5 10 1 8 0 0 Read More Sherlock HolmesXbox 360Must HavesGeek Gear Geek gear Over 100 Cases For Every Kind of iPhone User 2 days ago 10 Awesome Beach Accessories You Still Need This Year 4 days ago Samsung Galaxy S5 Cases Are Here 1 week ago 8 Phone Cases You Should Never Be Caught With 1 week ago Head Back to School With August's Tech Must Haves 3 weeks ago Over 60 Designer Cases to Outfit Your iPhone 3 weeks ago Get a Personalized Living Newsletter! Help us customize your newsletter by selecting your interests (optional): Love & Sex Tech Home Vegetarian 3210491 2 years I already saw season 2 of Sherlock, and it was awesome. Can't wait to see it again. savagecabbage 2 years Of course I want the Star Wars Xbox. Of course. monoblue 2 years I want. Sara-Yoo 2 years I cannot wait for Sherlock season 2! Robert Downey, Jr. may be a quirkily charming version of the detective, but Benedict Cumberbatch is Holmes's ultimate modern incarnation! Assistant-Community-Manager 2 years I want the sensu brush! Link Love Microsensors are being developed for planes to detect trouble — Newser This is why your iMessage is sending you spam — ReadWrite 25 geektastic school supplies for back to school — The Mary Sue Chinese censorship may be more selective than you thought — BuzzFeed Tech 10 of the best organizational apps for parents — Cool Mom Tech 6 geniuses who saw their inventions turn evil — Cracked The Evermind app lets you know when Grandma is making a cup of coffee — ChipChick Someone from the Harry Potter franchise has signed on for the spinoff — POPSUGAR Entertainment


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Right now, to update the outdated files in my crucible review, I navigate to individual files, see if the file is outdated(by looking out for 'File Outdated' link) and then add the latest revision to the review if I were the author/moderator. I'll like to know if I could update all the outdated files in a review in one click assuming I'm aware of what I do.
I did read into their docs about this, but there was no mention of such a thing. Do you all update the files individually as well? Any plugins out there that could help me update all outdated files in my crucible review?


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Support LCAC by purchasing a Macy's Shop for a Cause pass!
Shopping can be fun and help LCAC at the same time. Click here to learn more!
Raise a Glass of Hope!
Click here to learn about our next fundraiser for LCAC!
Wow, Lorton! Thanks for helping with Back to School!
263 families totaling 556 children were helped by you!! Drop off info for your donated backpacks can be found here!
National Night Out was a success!
Hundreds of Lorton area residents celebrated NNO last week. Click here to see pictures!
Welcome to LCAC
The Lorton Community Action Center (LCAC) seeks to provide low-income individuals, senior citizens and families residing in Fort Belvoir, Lorton, Newington and other portions of southeast Fairfax County with access to basic needs and the opportunity to empower themselves through LCAC's self-sufficiency programs. LCAC strives to connect people with other programs in the area that will have a positive impact on a family's long-term "health."
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We are listed under Lorton Community Action Center!
LCAC, P.O. Box 154, Lorton Virginia 22199-0154
Client Service Location- 9518 Richmond Highway
Hours - 8:30 am - 4:30 pm, Monday - Friday
703-339-5161 firstname.lastname@example.com For Virginia Relay, call 711.