Published by American Academy of Orthopaedic Surgeons

Online ISSN: 1526-632X


Print ISSN: 0028-3878


Decreased glutamate + glutamine in Alzheimer's disease detected in vivo with (1)H-MRS at 0.5 T
  • Article

April 2001


137 Reads




To determine whether glutamate + glutamine (GLX) levels in the brain as measured in vivo with proton MRS at 0.5 tesla (T) distinguish between probable Alzheimer's disease and normal aging. Glutamatergic markers had been measured previously in postmortem brain tissue. Conventional proton MRS at 1.5 T cannot reliably detect the GLX resonance in vivo. The authors developed a technique at 0.5 T that is sensitive to the GLX resonance. Metabolite ratios using creatine and phosphocreatine resonance as an internal standard were acquired from the cingulate region of 18 patients with AD and 12 healthy controls. The major resonances in the spectrum were examined: N-acetylaspartate (NAA), choline-containing compounds, myo-inositol, and GLX. The Mini-Mental State Examination (MMSE) was used to assess cognitive status. The Instrumental Activities of Daily Living Scale (Instrumental ADL) was used to assess functional status. Reduced ratios of GLX (-10%, p = 0.001) and NAA (-12%, p = 0.000) were found in patients with AD. Increased ratios of myo-inositol in patients with AD approached significance (+14%). GLX ratios of patients with AD were correlated with MMSE (r = 0.61, p = 0.007) and Instrumental ADL (r = 0.59, p = 0.01) scores. The combined sensitivity of NAA and myo-inositol in correctly diagnosing AD was 78%. The addition of GLX to NAA and myo-inositol increased the sensitivity to 89%. Overall diagnostic accuracy improved from 80 to 83% with the addition of GLX. Glutamate + glutamine reduction may be a biologic marker for AD and may be a potential aid in the early clinical diagnosis of AD.

Placebo-controlled study of the efficacy and safety of lamotrigine in patients with partial seizures. U.S. Lamotrigine Protocol 0.5 Clinical Trial Group
  • Article
  • Full-text available

December 1993


673 Reads






We evaluated the efficacy and safety of lamotrigine (300 and 500 mg/day) as add-on therapy in a multicenter, randomized, double-blind, parallel-group, placebo-controlled study of 216 patients with refractory partial seizures. During 6 months of treatment, median seizure frequency decreased by 8% with placebo, 20% with 300 mg lamotrigine, and 36% with 500 mg lamotrigine. Seizure frequency decreased by > or = 50% in one-third of the 500-mg group and one-fifth of the 300-mg group. Reductions in seizure frequency and seizure days were statistically significant, compared with placebo, for the 500-mg group but not the 300-mg group. Most adverse events were minor and resolved over time. Nine percent of patients on lamotrigine withdrew because of adverse experiences. Lamotrigine plasma concentrations appeared to be a linear function of dose, and the drug did not affect plasma concentrations of concomitant antiepileptic drugs. Lamotrigine was safe, effective, and well tolerated as add-on therapy for refractory partial seizures.

Short-lasting impairment of tactile perception by 0.9Hz-rTMS of the sensorimotor cortex

April 2003


50 Reads

To test whether low-frequency repetitive transcranial magnetic stimulation (rTMS) of sensorimotor cortex (SM1) has prolonged effects on somatosensory function, eight subjects were given 900 TMS pulses over the left hand SM1 (0.9Hz, 90% of the resting motor threshold) or at sites 3 cm anterior or posterior to it. Tactile threshold of the right hand was increased for a short duration after rTMS over SM1, but two-point discrimination and median nerve SEPs were unaffected after rTMS at any sites.

HIV DNA and cognition in a Thai longitudinal HAART initiation cohort: the SEARCH 001 Cohort Study

April 2009


67 Reads

The extent to which highly active antiretroviral therapy (HAART) era cognitive disorders are due to active processes, incomplete clearance of reservoirs, or comorbidities is controversial. This study aimed to determine if immunologic and virologic factors influence cognition after first-time HAART in Thai individuals with HIV-associated dementia (HAD) and Thai individuals without HAD (non-HAD). Variables were captured longitudinally to determine factors predictive of degree of cognitive recovery after first-time HAART. Neuropsychological data were compared to those of 230 HIV-negative Thai controls. HIV RNA and CD4 lymphocyte counts were not predictive of HAD cross-sectionally or degree of cognitive improvement longitudinally. In contrast, baseline and longitudinal HIV DNA isolated from monocytes correlated to cognitive performance irrespective of plasma HIV RNA and CD4 lymphocyte counts pre-HAART (p < 0.001) and at 48 weeks post HAART (p < 0.001). Levels exceeding 3.5 log(10) copies HIV DNA/10(6) monocyte at baseline distinguished all HAD and non-HAD cases (p < 0.001). At 48 weeks, monocyte HIV DNA was below the level of detection of our assay (10 copies/10(6) cells) in 15/15 non-HAD compared to only 4/12 HAD cases, despite undetectable plasma HIV RNA in 26/27 cases. Baseline monocyte HIV DNA predicted 48-week cognitive performance on a composite score, independently of concurrent monocyte HIV DNA and CD4 count (p < 0.001). Monocyte HIV DNA level correlates to cognitive performance before highly active antiretroviral therapy (HAART) and 48 weeks after HAART in this cohort and baseline monocyte HIV DNA may predict 48-week cognitive performance. These findings raise the possibility that short-term incomplete cognitive recovery with HAART may represent an active process related to this peripheral reservoir.

EHMTI-0055. Abnormal thalamic function in patients with vestibular migraine

May 2014


244 Reads

To investigate the functional response of neural pathways associated with vestibular stimulation in patients with vestibular migraine (VM). Twelve patients with VM underwent whole-brain blood oxygen level-dependent (BOLD) fMRI during ear irrigation with cold water. The functional response of neural pathways to this stimulation in patients with VM was compared with age- and sex-matched patients with migraine without aura and healthy controls. Secondary analyses explored associations between BOLD signal change and clinical features of migraine in patients. We observed a robust cortical and subcortical pattern of BOLD signal change in response to ear irrigation across all participants. Patients with VM showed a significantly increased thalamic activation in comparison with both patients with migraine without aura and healthy controls. The magnitude of thalamic activation was positively correlated with the frequency of migraine attacks in patients with VM. We provide novel evidence for abnormal thalamic functional response to vestibular stimulation in patients with VM. These functional abnormalities in central vestibular processing may contribute to VM pathophysiology.

A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease

June 2008


187 Reads

The safety and efficacy of istradefylline, a selective adenosine A(2A) receptor antagonist, was evaluated in a 12-week, double-blind study in levodopa-treated Parkinson disease (PD) subjects with motor complications. Levodopa-treated PD subjects (n = 395) received istradefylline 20 mg/day (n = 163), istradefylline 60 mg/day (n = 155), or placebo (n = 77) at 40 sites. The primary efficacy variable was the change in the percentage of time per day spent in the OFF state. Secondary measurements assessed change in ON time, Unified Parkinson's Disease Rating Scale, and Clinical Global Impression. Safety monitoring included clinical laboratory, electrocardiograms, vital signs, physical/neurologic examinations, and adverse events (AEs). Changes from baseline to endpoint in the percentage OFF time in the active groups compared with placebo were -4.35% (95% CI -8.16 to -0.54; p = 0.026) for istradefylline 20 mg/day and -4.49% (95% CI -8.35 to -0.62; p = 0.024) for 60 mg/day; these changes were significant (analysis of covariance). For total hours, istradefylline demonstrated mean differences from placebo of -0.64 hours (95% CI -1.30 to 0.01) for 20 mg/day and -0.77 hours (95% CI -1.44 to -0.11) for 60 mg/day (p = 0.065; overall treatment effect). Clinical response occurred by the second week and was maintained throughout the study. Istradefylline was well tolerated. The common AEs were dyskinesia, nausea, dizziness, and hallucinations. Istradefylline demonstrated a significant reduction in the percentage of awake time per day spent in the OFF state, which resulted in a clinically meaningful reduction in OFF time, without an increase in ON time with troublesome dyskinesia, and was well tolerated as adjunctive treatment to levodopa in Parkinson disease.

Congenital mUscUkdr dystrophy: Clinical and pathologic study 01' 50 patients with the classical (Occidental) merosin-positive form

April 1996


27 Reads

We studied 50 patients with the merosin-positive form of congenital muscular dystrophy (MP-CMD) clinically and pathologically. The frequency of MP-CMD in our laboratory was approximately one-half that of the Fukuyama type and one-sixth that of Duchenne muscular dystrophy. The early signs of MP-CMD included decreased fetal movement during pregnancy (14%) and poor suck (42%), floppiness (30%), and respiratory difficulty (16%) in early infancy. Eighty-six percent of the patients had delayed motor development. Ninety-two percent of the patients followed beyond age 4 years had learned to walk. The disease was relatively slowly progressive, except in six patients who rapidly lost ambulation. Almost all patients had normal IQ, except four who were mildly to moderately retarded. Of the patients examined by cranial CT/MRI, 24% showed cerebral atrophy and 11% had areas of white matter lucency. Muscle biopsy results in those younger than 5 years showed mild dystrophic changes consisting of variation in fiber size and scattered necrotic and regenerating fibers. In older children, there were additional chronic dystrophic changes, including fiber splitting (32%), moth-eaten appearance (32%), marked fatty replacement (46%), and abnormal fiber type distribution (59%). The manifestations of MP-CMD were generally milder and more slowly progressive than those of the Fukuyama type and merosin-negative form of congenital muscular dystrophy.

Optimizing the dose of zolmitriptan (Zomig, 311C90) for the acute treatment of migraine. A multicenter, double-blind, placebo-controlled, dose range-finding study. The 017 Clinical Trial Study Group

November 1997


43 Reads

This study investigated the efficacy of zolmitriptan (Zomig, formerly 311C90) in acute migraine therapy. Patients with a history of migraine were randomized in a double-blind, multicenter, placebo-controlled, dose range-finding study of oral zolmitriptan 1, 2.5, 5, or 10 mg versus placebo for the treatment of a severe or moderate migraine headache. Patients with persistent or recurrent headache 4 to 24 hours after the initial dose, who did not take escape medication, were eligible to receive a second blinded dose of either zolmitriptan or placebo. Of 1,144 patients treated, 999 evaluable patients completed the study. The headache response rates with zolmitriptan doses > or = 2.5 mg were 44 to 51% at 1 hour, 65 to 67% at 2 hours, and 75 to 78% at 4 hours (all significantly superior to placebo). Also, zolmitriptan effectively relieved migraine-associated symptoms such as nausea, photophobia and phonophobia, and reduced activity impairment. Rates of headache recurrence, headache persistence, and use of escape medication were lower with zolmitriptan doses > or = 2.5 mg than with placebo. In patients with persistent or recurrent headache, a second zolmitriptan dose effectively treated both headache and nonheadache symptoms. Zolmitriptan was well tolerated, with a lower incidence of adverse events being reported with doses < or = 2.5 mg than with those > or = 5 mg. Zolmitriptan is a well tolerated and effective acute migraine therapy providing rapid relief of migraine headache within 1 hour. A clear dose-response relationship between efficacy and tolerability suggests that 2.5 mg is the optimal initial dose for the acute treatment of a migraine attack.

Neuropsychological abnormalities in patients with dementia in CRF 01_AE HIV-1 infection

March 2007


67 Reads

HIV-associated dementia (HAD) is not firmly established in patients with circulating recombinant form (CRF) 01_AE HIV-1. In this study, we compared neuropsychological performance among 15 Thai individuals with HAD, 15 Thai individuals without HAD, and 30 HIV-negative control subjects. HIV-1 participants were highly active anti-retroviral therapy naive and matched by age, education, and CD4 count. Neuropsychological testing abnormalities were identified in most cognitive domains among HAD vs HIV-negative participants, confirming the presence of HAD in CRF01_AE.

Effects of a HLA-B*15:02 screening policy on antiepileptic drug use and severe skin reactions

October 2014


73 Reads

Objective: To assess the effects of an active pharmacogenetic screening policy for antiepileptic drug (AED) therapy on everyday clinical practice and clinical outcomes. Methods: We extracted data covering all public hospitals and clinics in Hong Kong for patients who were newly commenced on carbamazepine or other AEDs, or were tested for HLA-B*15:02 3 years before policy implementation (prepolicy: September 16, 2005 to September 15, 2008) and 3 years after (postpolicy: September 16, 2008 to September 15, 2011). We compared AED prescriptions and the incidence of SJS/TEN between the 2 periods and analyzed adherence to the policy. Results: A total of 111,242 patients were included and 4,149 were tested for HLA-B*15:02. As a proportion of all new AED prescriptions, carbamazepine declined from 16.2% (10,077/62,056) in the pre-policy period to 2.6% (1,910/74,606) in the post-policy period (p < 0.001) while other AEDs increased. Among patients started on their first-ever AEDs, incidence of Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) induced by carbamazepine reduced from 0.24% (20/8,284) to 0% (0/1,076; p = 0.027), but SJS/TEN induced by phenytoin increased (0.15% [18/11,839] vs 0.26% [33/12,618], p = 0.058), and the overall incidence of AED-induced SJS/TEN remained unchanged (0.09% [42/45,832] vs 0.07% [39/55,326], p = 0.238). Test-prescription practice was adherent to the policy in only 26.4% (1,302/4,929) of relevant patients. Conclusions: The screening policy was associated with prevention of carbamazepine-induced SJS/TEN without reducing the overall burden of AED-induced SJS/TEN, likely because of clinicians preferring AEDs that do not require genetic screening but may also induce SJS/TEN.

HLA-DQB1 genotype in Sardinian multiple sclerosis: Evidence for a key role of DQB1 *0201 and *0302 alleles

May 1992


30 Reads

We studied HLA-DQB1 haplotypes in 103 unrelated multiple sclerosis (UMS) patients and in 26 related (RMS) patients from 12 families from Sardinia, Italy, where the disease was associated with the HLA-DR4 allele. Using polymerase chain reaction and allele-specific oligonucleotide probes, we found in UMS an increased frequency of the DQB1 *0201 (p = 0.010) and DQB1 *0302 (p = 0.025) alleles, whereas the DQB1 *0301 allele was significantly decreased (p = 0.027). In RMS, only the DQB1 *0302 allele was increased (p = 0.047), and no difference was found in the DQB1 *0301 allele. For DQB haplotypes, an increased frequency of DQB1 *0302/*0502 (p = 0.026) and a decreased frequency of DQB1 *0201/*0601 (p = 0.009) and DQB1 *0502/*0502 (p = 0.025) was found in UMS patients, whereas RMS patients showed an increased frequency of DQB1 *0301/*0302 (p = 0.005). Because DQB1 *0201 and *0302 alleles are increased in Caucasian MS patients, where the disease is related to HLA-DR2 and where a primary association with the HLA-DR2, DQB1 *0602 allele has been reported, we conclude that Caucasian and Sardinian populations share HLA-DQB1 *0201 and *0302 alleles in genetic susceptibility to MS.

and the Vigabatrin Protocol 024 Investigative Cohort. A double-blind. placebo-controlled study of vigabatrin 3 g/day in patients with uncontrolled partial seizures

February 1996


44 Reads

This study compared the efficacy and tolerability of vigabatrin 3 g/day as add-on therapy with that of placebo in patients with focal epilepsy whose complex partial seizures were difficult to control with established antiepilepsy drug therapy. We enrolled 203 patients; 182 (90 placebo; 92 vigabatrin) received drug therapy under double-blind conditions. We increased the daily dosage to 2.5 g/day during a 4-week titration segment and maintained it at 3 g/day during the 12-week maintenance segment. By analyses we found a statistically significant lower frequency of seizures (complex seizures plus partial seizures secondarily generalized) at the end of the study for patients receiving vigabatrin than for those receiving placebo. The median monthly frequency was reduced by three seizures per 28 days in the vigabatrin group (baseline, 8.3; end of study, 5.3) versus 0.8 seizures per 28 days in the placebo group (baseline, 8.3; end of study, 7.5) (p = 0.0002). Therapeutic success (a 50% reduction from baseline in mean monthly seizure frequency) was attained in 40 of the vigabatrin patients (43%) compared with 17 of those treated with placebo (19%) (p < 0.001). Vigabatrin significantly increased the mean number of seizure-free days per 28 days (2.2 days) compared with placebo (0.5 days) (p = 0.0024). Mean trough serum vigabatrin concentration during therapy was 8.6 +/- 7.7 micro g/ml. The oral clearance of vigabatrin was determined to be 7.8 L/hr, and the elimination half-life was 8.4 hours. No clinically important changes in MRI, evoked potential, or other laboratory tests were noted during vigabatrin treatment. The results of this study indicate that 3 g/day vigabatrin is more effective than placebo as add-on therapy. Vigabatrin was well tolerated, compliance was high with twice-daily administration, and therapy did not result in clinically relevant drug interactions. NEUROLOGY 1996;46: 54-61

Clinical efficacy and tolerability of 2.5 mg zolmitriptan for the acute treatment of migraine. The 042 Clinical Trial Study Group

November 1997


18 Reads

Previous studies demonstrated that zolmitriptan at doses of 1 to 25 mg was highly effective in treating acute migraine attacks. The 2.5-mg dose had a favorable therapeutic effect with high efficacy and good tolerability. The objective of this study was to further evaluate the efficacy of a single 2.5-mg dose of zolmitriptan (Zomig, formerly known as 311C90) for acute treatment of a single moderate or severe migraine attack. The study was a randomized, double-blind, placebo-controlled clinical trial. Female and male patients, 12 to 65 years old, with migraine (with or without aura) for > or = 1 year, one to six migraines per month, and age at onset < 50 years were included; 327 patients were screened and randomized to receive either zolmitriptan (n = 219) or placebo (n = 108). Patients treated a single moderate or severe migraine headache with 2.5 mg zolmitriptan or placebo and recorded clinical efficacy and adverse events on a diary form. Headache response at 2 hours was 62% for zolmitriptan compared with 36% for placebo (p < 0.001); at 4 hours, headache response was 70% with zolmitriptan and 37% with placebo (p < 0.001). Headache recurrence in patients treated with 2.5 mg zolmitriptan was 22% (versus placebo 30%). The headache response at 4 hours, pain-free rate, and response rate of nonheadache symptoms favored zolmitriptan over placebo. No serious adverse events were associated with zolmitriptan treatment. A 2.5-mg dose of zolmitriptan is clinically effective and well tolerated for the acute treatment of migraine.

P.P.5 06 A mutation in the fast skeletal muscle Troponin I gene causes myopathy and distal arthrogryposis

September 2006


46 Reads

To describe a three-generation family with distal arthrogryposis associated with myopathy and caused by a mutation in the gene encoding for sarcomeric thin filament protein troponin I, TNNI2. The authors performed clinical investigations and reviewed medical records. Muscle biopsy specimens were obtained for morphologic analysis. Genomic DNA was extracted from blood and analyzed for mutations in TNNI2. The five affected individuals had predominantly distal congenital joint contractures, mild facial involvement (mild micrognathia, narrow palpebral fissures), and no detectable muscle weakness. The four affected adults had slightly increased levels of creatine kinase in blood, and muscle biopsy specimens showed findings of myopathy with changes restricted to type 2 fibers. These included variability of muscle fiber size, internalized nuclei, and increased interstitial connective tissue. Analysis of TNNI2 encoding the troponin I isoform expressed in type 2 muscle fibers disclosed a heterozygous three-base in-frame deletion, 2,918-2,920del, skipping the highly conserved lysine at position 176. The mutation was present in all 5 affected individuals but was not identified in any of the 11 unaffected family members. Distal arthrogryposis type 1 is genetically heterogeneous, and myopathy due to sarcomeric protein dysfunction may be one underlying cause of the disease.

HLA DR15 (DR2) and DQB1*0602 typing studies in 188 narcoleptic patients with cataplexy

July 1997


27 Reads

Narcolepsy is considered a homogeneous clinical entity when excessive daytime sleepiness and cataplexy are present. Cataplexy is a polymorphic symptom that can be very mild and is thus subjectively defined. The Multiple Sleep Latency Test (MSLT) is widely used as a diagnostic test for narcolepsy. A short mean sleep latency and multiple sleep onset REM periods (SOREMPs) are typically observed in narcoleptic patients. The discovery of a tight association of narcolepsy with HLA class II antigens offers a unique opportunity to explore the respective value of the MSLT or of the presence of clear-cut cataplexy in defining an etiologically homogeneous group of narcoleptic patients. In this study, we carried out HLA typing for DR15(DR2) and DQB1*0602 in 188 narcoleptic patients with cataplexy in three ethnic groups (24 Asians, 61 Blacks, and 103 Caucasians). These results confirm the importance of DQB1*0602 typing rather than DR15 (DR2) typing in Black narcoleptic patients and demonstrate that the presence of clear-cut cataplexy is a better predictor for DQB1*0602 positivity than the presence of abnormal MSLT results.

DQB1*0602 predicts interindividual differences in physiologic sleep, sleepiness, and fatigue

October 2010


61 Reads

The human leukocyte antigen (HLA) DQB1*0602 allele is closely associated with narcolepsy, a neurologic disorder characterized by excessive daytime sleepiness, fragmented sleep, and shortened REM sleep latency. We evaluated whether DQB1*0602 was a novel marker of interindividual differences by determining its relationship to sleep homeostatic, sleepiness, and cognitive responses to baseline and chronic partial sleep deprivation (PSD) conditions. Ninety-two DQB1*0602-negative and 37 DQB1*0602-positive healthy adults participated in a protocol of 2 baseline 10 hours time in bed (TIB) nights followed by 5 consecutive 4 hours TIB nights. DQB1*0602 allelic frequencies did not differ significantly between Caucasians and African Americans. During baseline, although DQB1*0602-positive subjects were subjectively sleepier and more fatigued, they showed greater sleep fragmentation, and decreased sleep homeostatic pressure and differentially sharper declines during the night (measured by non-REM EEG slow-wave energy [SWE]). During PSD, DQB1*0602-positive subjects were sleepier and showed more fragmented sleep, despite SWE elevation comparable to negative subjects. Moreover, they showed differentially greater REM sleep latency reductions and smaller stage 2 reductions, along with differentially greater increases in fatigue. Both groups demonstrated comparable cumulative decreases in cognitive performance. DQB1*0602 positivity in a healthy population may represent a continuum of some sleep-wake features of narcolepsy. DQB1*0602 was associated with interindividual differences in sleep homeostasis, physiologic sleep, sleepiness, and fatigue-but not in cognitive measures-during baseline and chronic PSD. Thus, DQB1*0602 may represent a genetic biomarker for predicting such individual differences in basal and sleep loss conditions.

Treatment of Parkinson's Disease with 8-alpha-amino-ergoline, CU32-085

May 1983


11 Reads

8-alpha-amino-ergoline (CU 32-085) is a dopamine receptor agonist that should have fewer side effects than most other dopamine agonists. We studied the effect of this drug in 19 parkinsonian patients. In untreated or levodopa-treated patients, there was considerable improvement of akinesia, rigidity, and tremor; on-off symptoms also improved in the levodopa-treated patients. In patients pretreated with levodopa/bromocriptine, about half the dose of CU 32-085 was necessary to obtain the same therapeutic results, but there was no further improvement of on-off symptoms. Side effects were less pronounced than with bromocriptine; no circulatory disturbances and no psychotic episodes were observed.

Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine

May 2008


306 Reads

To determine an effective and tolerable dose of a novel oral calcitonin gene-related peptide (CGRP) receptor antagonist, MK-0974, for the acute treatment of migraine. Randomized, double-blind, parallel-group, clinical trial with a two-stage, adaptive, dose-ranging design. Patients were allocated to treat a moderate or severe migraine attack with MK-0974 (25, 50, 100, 200, 300, 400, or 600 mg), rizatriptan 10 mg, or placebo taken orally. The primary endpoint was pain relief (reduction to mild or none) 2 hours after dosing. Secondary endpoints included pain freedom at 2 hours and sustained pain relief at 24 hours. A prespecified, blinded, automated interim analysis was used to discontinue randomization to less effective doses. Per the adaptive study design, the four lowest MK-0974 groups (25, 50, 100, 200 mg) were discontinued due to insufficient efficacy. For the remaining treatment groups, the estimated pain relief proportions at 2 hours were 300 mg (n = 38) 68.1%, 400 mg (n = 45) 48.2%, 600 mg (n = 40) 67.5%, rizatriptan 10 mg (n = 34) 69.5%, and placebo (n = 115) 46.3%. The prespecified primary efficacy hypothesis test, which compared the average 2-hour pain relief response proportion of the combined 300, 400, and 600 mg MK-0974 groups to placebo, was significant (P = 0.015). A generally similar efficacy pattern was seen for other endpoints. MK-0974 was generally well tolerated and there did not appear to be an increase in adverse events with increasing dose. The novel, orally administered calcitonin gene-related peptide (CGRP) receptor antagonist, MK-0974, was effective and generally well tolerated for the acute treatment of migraine.

Cerebellar atrophy following acute 0intoxication with phenytoin

April 1989


14 Reads

A patient developed marked cerebellar atrophy after a single suicidal intoxication with 7 grams phenytoin. The clinical signs of cerebellar dysfunction subsided very slowly and incompletely within 18 months. We documented the cerebellar atrophy by CTs 4 weeks and 1 year after the intoxication, and we suggest that a single severe acute intoxication with phenytoin may directly cause cerebellar degeneration.

Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 600-, 800-, and 1,000-mg daily dosages. Topiramate YE Study Group

June 1996


45 Reads

We conducted a multicenter, double-blind, randomized, parallel, placebo-controlled trial in 190 patients to evaluate the safety and efficacy of three dosages of topiramate (600, 800, and 1,000 mg/day) as adjunctive therapy for patients with refractory partial epilepsy. During an 18-week double-blind treatment period, median percent reductions from baseline in average monthly seizure rates were 1% for placebo, 41% for topiramate 600 mg/day and topiramate 800 mg/day, and 38% for topiramate 1,000 mg/day. There was a 50% or greater reduction from baseline in seizure frequency in 9% of patients in the placebo group and in 44% for topiramate 600 mg/day, 40% for topiramate 800 mg/day, and 38% for topiramate 1,000 mg/day. No placebo patients were improved by 75 to 100% in seizure frequency, whereas 20% of the topiramate patients were improved to this degree. All intent-to-treat drug-placebo comparisons including seizure reduction, percent responders, and investigator and patient global evaluations significantly (p <or=to 0.02) favored topiramate. Treatment-emergent adverse events consisted mainly of neurologic symptoms commonly observed during antiepileptic drug (AED) therapy. Sixteen percent of patients on topiramate discontinued therapy due to adverse events. Results of this study indicate that topiramate is a highly efficacious and generally well tolerated new AED. When large groups of patients are compared, incremental efficacy in the add-on setting is not observed at topiramate dosages above 600 mg/day; however, higher doses may prove beneficial to individual patients who tolerate them. NEUROLOGY 1996;46: 1678-1683

1,1' -Ethylidenebis- [tryptophan] induces pathologic alterations in muscle similar to those observed in the eosinophilia-myalgia syndrome

January 1995


52 Reads

1,1'-Ethylidenebis[tryptophan] (EBT), a derivative of L-tryptophan (LT), is a trace contaminant in batches of LT implicated by epidemiologic evidence in the pathogenesis of the eosinophilia-myalgia syndrome (EMS). We treated female Lewis rats with EBT or unimplicated LT (4 mg per 100 grams daily) by intraperitoneal injection. No rash or weakness occurred in either group. All three EBT rats had a few necrotic muscle fibers. In two rats, perimysium and fascia were abnormally thickened and infiltrated with lymphocytes, macrophages, and sparse eosinophils; two rats had sparse perineurial inflammatory cells. Rats treated with unimplicated LT showed no abnormality. These findings replicate an important feature of human EMS and support the epidemiologic evidence linking EBT to the pathogenesis of the human disease.

Mild parkinsonism in persons exposed to 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)

December 1989


18 Reads

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) produces moderate to severe parkinsonism in humans, but has not been reported to cause a syndrome similar to early Parkinson's disease. We now report 22 cases of mild parkinsonism resulting from exposure to MPTP.

Permanent human Parkinson's due to 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP): seven cases

August 1985


167 Reads

Seven patients developed chronic and severe parkinsonism after repeatedly injecting 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intravenously. Levodopa and bromocriptine controlled the symptoms; however, within months, five of the seven patients experienced dyskinesias or on-off fluctuations. Therefore, neither prolonged levodopa treatment nor progressive disease was necessary for on-off phenomena. Because the neurotoxic effects of MPTP seem limited to the substantia nigra, damage to this system alone may produce all the motor features of Parkinson's disease. MPTP differs from other neurotoxins in that it consistently produces a pure parkinsonian state.

Single photon emission computed tomography (SPECT) brain imaging using N,N,N'-trimethyl-N'-(2 hydroxy-3-methyl-5-123Iiodobenzyl)-1,3-propanediamine 2 HCl (HIPDM): Intractable complex partial seizures

December 1986


36 Reads

HIPDM-SPECT brain imaging was performed in four patients with intractable complex partial seizures (CPS). Three patients had an epileptogenic focus in one temporal lobe and underwent anterior temporal lobectomy. Interictal HIPDM-SPECT demonstrated decreased regional cerebral perfusion (rCP) in the epileptogenic area in only one patient, but ictal studies showed increased rCP in the epileptic foci of all three patients. In the fourth patient, interictal HIPDM-SPECT showed increased rCP in the area of epileptogenic focus; when antiepileptic medication was taken, rCP decreased. HIPDM-SPECT brain imaging is useful for localizing epileptogenic foci in CPS.

Amyloid deposition is decreasing in aging brains: An autopsy study of 1,599 older people

December 2013


91 Reads

To explore cohort effects on age- and Alzheimer disease (AD)-related neuropathologic changes. We compared amyloid deposition in autopsied cases aged 65 years and older who died between 1972 and 2006. We included consecutive cases for 1972-1975, 1980, 1985, 1990, 1995, and 2000-2006. We used linear regression models to assess period effects after adjustment for age, cognitive status, and neurofibrillary tangle (NFT) staging. We calculated amyloid/NFT stage ratios to account for possible changes in AD prevalence/severity over time. Mean amyloid stage was significantly related to year of death (p = 0.001) in the total population (1,599 cases, mean age 82 ± 8 years) and decreased 24%, from 1.88 ± 0.89 to 1.57 ± 0.81 (p < 0.0001), in 1,265 individuals without dementia. This decrease was particularly marked in the oldest age groups; people 85 years and older in 2006 had less amyloid deposition compared with those aged 75 to 84 years in 1972. Recent cohorts had lower amyloid deposition. The amyloid/NFT stage ratio decreased from 1.51 ± 0.74 to 0.99 ± 0.56 (p < 0.0001) in cases without dementia and from 0.74 ± 0.13 to 0.56 ± 0.21 (p = 0.0019) in individuals with dementia, confirming that more recent cases had less amyloid despite higher NFT densities. Cohort effects were highly significant (p < 0.0001). The strong cohort effect we describe may influence the performance of early amyloid-based AD markers. It also provides preclinical evidence supporting recently described decreases in AD incidence. This trend, if confirmed in community-based studies, may lead to new insights in our understanding of both normal and pathologic brain aging.

Intra-blood-brain barrier synthesis of IgG: Comparison of IgG synthesis formulas in a computer model and in 1,629 consecutive specimens

April 1992


5 Reads

We evaluated four formulas for estimating the intra-blood-brain barrier (IBBB) synthesis of IgG in a computer model of two types of BBB damage and in 1,629 consecutively received pairs of CSF and serum. These four formulas were the IgG synthesis rate (SR), IgG(loc) (ie, local), IgG index, and IgG extended index. Results from the 1,629 specimens and the computer model of type 2 BBB damage (partial or total loss of selective filtration) accurately predicted problems encountered with the IgG SR in clinical practice. In both the model and with the results from the 1,629 specimens, the combination of the IgG(loc) and IgG index formulas minimized the possibility of false-positive and false-negative results and yielded the most reliable results for IBBB synthesis of IgG in the presence or absence of increased permeability of the BBB. Additional studies with detailed clinical correlations will allow an accurate assessment of how effectively this combination of formulas can help to rule in or out the diagnosis of a particular disease or inflammatory condition of the CNS.

Inter- and intrarater scoring agreement using grades 1.0 to 3.5 of the Kurtzke Expanded Disability Status Scale (EDSS). Multiple Sclerosis Collaborative Research Group

May 1992


38 Reads

We determined inter- and intrarater Kurtzke Expanded Disability Status Scale (EDSS) scoring agreement for four trained examining physicians who evaluated 10 clinically stable multiple sclerosis patients. These patients had previously been determined to have EDSS scores of 1.0 to 3.5 and were scheduled to participate in a funded clinical trial of intramuscular recombinant interferon-beta. Intrarater reliability was greater than interrater reliability for scoring the EDSS and all of its component functional systems scores (FSS). Specifically, individual examiners were able to reproduce three serial examination scores on the same patient on the same day (intrarater agreement) within 1.0 EDSS or 2.0 individual FSS points. Reproducible scoring across examiners (interrater agreement), however, could only be accomplished within 1.5 EDSS or 3.0 individual FSS points. Additionally, the interrater scoring variability in our patients is greater than that previously reported for patients with higher EDSS scores. We conclude that clinical trials that employ the EDSS as an outcome measure of treatment efficacy should include inter- and intrarater agreement data for all examining physicians. Most importantly, studies using a single examining physician to evaluate individual patients throughout the course of a clinical trial will require less change in the EDSS to reliably measure disease activity than will studies using more than one examining physician to evaluate individual patients throughout the trial.

Preclinical Alzheimer disease: Neuropsychological test performance 1.5 to 8 years prior to onset

January 2005


109 Reads

To determine if individuals ultimately diagnosed with Alzheimer disease (AD) exhibited evidence of cognitive impairment on neuropsychological tests administered between 1.5 years and 8.1 years before dementia onset. A total of 693 community-dwelling individuals, part of the Cardiovascular Health Study, completed a neuropsychological test battery in 1991/92. Subjects were followed annually over the next 8 years (median follow-up = 7.4 years). Seventy-two individuals were ultimately diagnosed with AD (median follow-up = 4.5 years): 24 with AD onset 1.5 to 3.4 years after baseline neuropsychological testing, 20 with AD onset 3.5 to 5.0 years after testing, and 28 with onset 5.1 to 8.1 years after testing. A total of 621 individuals remained nondemented throughout the 8 years of follow-up (median follow-up = 7.5 years). Subjects ultimately diagnosed with AD had poorer scores on baseline neuropsychological measures than subjects who remained nondemented. Although individuals closest to AD onset (i.e., 1.5 to 3.4 years) performed the most poorly, cognitive impairment was detected in individuals who did not develop AD until 5 to 8 years later. Cognitive changes can be detected well before onset of Alzheimer disease.

Diffusion-weighted MRI in acute stroke within the first 6 hours: 1.5 or 3.0 Tesla?

June 2010


328 Reads

To compare the sensitivity and specificity of 1.5-T and 3.0-T diffusion-weighted MRI (DWI) to detect hyperacute ischemic stroke lesions. We blindly reviewed the DWI of 135 acute stroke patients and 34 controls performed at 1.5 T (n = 108) or 3.0 T (n = 61). The stroke patients all had subsequently proved carotid territory ischemic stroke and were imaged within the first 6 hours after stroke onset. Four readers (2 neuroradiologists and 2 stroke neurologists) blinded to clinical data and magnetic field strength recorded the presence of ischemic lesions on DWI and apparent diffusion coefficient (ADC) maps if necessary. Sensitivity, specificity, and false-negative rates were computed. Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and DWI contrasts were calculated at both field strengths. The accuracy of DWI in stroke diagnosis was superior at 1.5 T (98.8%) than at 3.0 T (90.9%, p = 0.03). The sensitivity decreased from 99.1% at 1.5 T to 92.5% at 3.0 T (p = 0.06) and the specificity from 97.8% to 84.1% (p = 0.002). ADC map readings did not improve accuracy, sensitivity, or specificity. The false-negative rate was 0.6% at 1.5 T and 6.1% at 3.0 T. Type of readers, stroke severity, and type of the coil did not affect diagnosis value. SNR and CNR were significantly higher at 3 T (p < 0.0001) but DWI contrast was lower (p = 0.04). Blind reading by 4 experts of a large series of images shows that 1.5-T diffusion-weighted MRI (DWI) is better than 3.0-T DWI for the imaging of hyperacute stroke during the therapeutic window of thrombolysis.

Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group IFNB MS Study Group Neurology 1993 43 655 661 10.1212/WNL.43.4.655

January 2002


341 Reads

We performed yearly MRI analyses on 327 of the total 372 patients in a multicenter, randomized, double-blind, placebo-controlled trial of interferon beta-1b (IFNB). Clinical results are presented in the preceding companion paper. Baseline MRI characteristics were the same in all treatment groups. Fifty-two patients at one center formed a cohort for frequent MRIs (one every 6 weeks) for analysis of disease activity. The MRI results support the clinical results in showing a significant reduction in disease activity as measured by numbers of active scans (median 80% reduction, p = 0.0082) and appearance of new lesions. In addition, there was an equally significant reduction in MRI-detected burden of disease in the treatment as compared with placebo groups (mean group difference of 23%, p = 0.001). These results demonstrate that IFNB has made a significant impact on the natural history of MS in these patients.

Tremor in Parkinson's disease and serotonergic dysfunction: An 11C-WAY 100635 PET study

February 2003


316 Reads

The pathophysiologic mechanisms underlying parkinsonian tremor remain unclear. The response to dopaminergic treatment is variable and nondopaminergic mechanisms may play a role in tremor generation. Midbrain raphe 5-HT(1A) binding provides a functional measure of serotonergic system integrity. With PET, the aim of this study was to examine regional cerebral (11)C-WAY 100635 binding to 5-HT(1A) receptors in patients with PD and to correlate it with severity of tremor. (11)C-WAY 100635 PET was performed on 23 patients with PD and eight age-matched healthy volunteers. Brain 5-HT(1A) receptor binding was computed using compartmental modeling with a cerebellar reference tissue input function. The authors found mean 27% reduction in the midbrain raphe 5-HT(1A) binding potential in patients with PD compared to healthy volunteers (p < 0.001). They also showed that Unified Parkinson's Disease Rating Scale composite tremor scores, but not rigidity or bradykinesia, correlate with 5-HT(1A) binding in the raphe (p < 0.01). These findings support previous indirect evidence that serotonergic neurotransmission is decreased in PD in vivo. The authors hypothesize that the reduction in raphe 5-HT(1A) binding represents receptor dysfunction or loss of cell bodies due to Lewy body degeneration in PD, or both. An association between 5-HT(1A) receptor availability in the raphe and severity of parkinsonian tremor was also found.

Protein S-100b serum levels in trauma-induced brain death

March 2003


55 Reads

To analyze the time course of serum protein S-100b in patients with traumatic brain injury deteriorating to brain death and to investigate the predictive value of initial S-100b levels in relation to clinical and radiologic measures of injury severity with regard to brain death. Forty-seven patients who sustained severe head injury were studied. Blood samples for measurement of S-100b were drawn on admission in the intensive care unit and every 24 hours thereafter for a maximum of 6 consecutive days or until brain death occurred. Variables related to outcome were recorded, including age, sex, Glasgow Coma Scale (GCS), and brain CT findings on admission. Outcome was defined as deterioration to brain death or not. Of the 47 patients studied, 17 deteriorated to brain death and 30 did not. On admission, patients who became brain dead had higher median serum S-100b levels compared with those who did not (2.32 microg/L vs 1.04 micro g/L, p = 0.0028). Logistic regression analysis showed that initial S-100b was an independent predictor of brain death (p = 0.041), in the presence of advanced age (p = 0.043) and low GCS score (p = 0.013). The odds ratio of 2.09 (95% CI, 1.03 to 4.25) indicates a more than doubling of the probability of deteriorating to brain death per 1- micro g/L increase in S-100b on admission. At clinical brain death, median S-100b was higher in patients with brain death compared with the peak S-100b value obtained over a 6-day period in those who did not become brain dead (6.58 microg/L vs 1.49 microg/L, p < 0.0001). Prediction of brain death after severe head injury can be improved by combining clinical and S-100b data; thus, serum S-100b determination deserves to be included in the neuromonitoring of patients with severe traumatic brain injury.

G.P.101 New immunohistochemical method for improved myotonia and chloride channel mutation diagnostics

November 2012


32 Reads

Objective: The objective of this study was to validate the immunohistochemical assay for the diagnosis of nondystrophic myotonia and to provide full clarification of clinical disease to patients in whom basic genetic testing has failed to do so. Methods: An immunohistochemical assay of sarcolemmal chloride channel abundance using 2 different ClC1-specific antibodies. Results: This method led to the identification of new mutations, to the reclassification of W118G in CLCN1 as a moderately pathogenic mutation, and to confirmation of recessive (Becker) myotonia congenita in cases when only one recessive CLCN1 mutation had been identified by genetic testing. Conclusions: We have developed a robust immunohistochemical assay that can detect loss of sarcolemmal ClC-1 protein on muscle sections. This in combination with gene sequencing is a powerful approach to achieving a final diagnosis of nondystrophic myotonia.

The minor symptoms of increased intracranial pressure: 101 patients with benign intracranial hypertension

October 1988


267 Reads

Of 101 patients with benign intracranial hypertension not related to vasculitis, neck stiffness occurred in 31, tinnitus in 27, distal extremity paresthesias in 22, joint pains in 13, low back pain in 5, and gait "ataxia" in 4. Symptoms resolved promptly upon lowering the intracranial pressure by lumbar puncture, and were probably directly caused by intracranial hypertension. Awareness of these "minor" symptoms of increased intracranial pressure can facilitate diagnosis and management.

Antithrombotic treatment of ischemic stroke among patients with occlusion or severe stenosis of the internal carotid artery: A report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST)

July 1999


59 Reads

To examine the responses to early IV administration of an anticoagulant or placebo started within 24 hours of stroke among persons with an ipsilateral occlusion or severe stenosis of the internal carotid artery (ICA) identified by carotid duplex imaging. Patients with ischemic stroke of the cerebral hemisphere secondary to an ipsilateral occlusion or severe stenosis of the ICA generally have a poor prognosis. Early, accurate identification of these patients might permit improved treatment. Exploratory analysis of outcomes at 7 days and 3 months was performed among patients enrolled in the Trial of Org 10172 in Acute Stroke Treatment (TOAST) who had an ischemic stroke in the cerebral hemisphere ipsilateral to an occlusion or a stenosis >50% of the ICA identified by carotid duplex imaging. Regardless of treatment, patients with duplex evidence of an occlusion of the ICA had more severe strokes and poorer outcomes at 7 days and 3 months than patients who had a stenosis. Favorable outcomes at 7 days were noted in 64 of 119 patients given danaparoid (53.8%) and 41 of 108 patients treated with placebo (38.0%; p = 0.023). By 3 months, favorable outcomes were noted in 82 patients given danaparoid (68.3%) and 58 patients administered placebo (53.2%; p = 0.021). Early identification by duplex imaging of an occlusion or severe stenosis of the ICA ipsilateral to a hemispheric ischemic stroke might improve selection of patients who could be treated with emergent anticoagulation. Further testing of this approach is needed.

A dose escalation study of ORG 10172 (low molecular weight heparinoid) in stroke

March 1989


28 Reads

An intravenous infusion of a low molecular weight heparinoid, with a reduced risk of hemorrhage, may be an alternative to heparin in the management of acute ischemic stroke. To evaluate this hypothesis, we studied the safety of the heparinoid, ORG 10172, in a dose-escalation study in 26 patients. The drug was administered as a loading bolus followed by a 7-day infusion in five rates with target anti-factor Xa levels from 0.2 to 1.0 U/ml. The drug was well tolerated; no major bleeding complications or thrombocytopenia occurred. There were no deaths or hemorrhagic transformation of cerebral infarctions. The results indicate that ORG 10172 at doses to achieve a level of 1.0 U/ml or less may be used safely in management of acute cerebral infarction.

Accuracy of initial stroke subtype diagnosis in the TOAST study. Trial of ORG 10172 in Acute Stroke Treatment

December 1995


23 Reads

Rapid identification of stroke subtype is valuable for both practicing clinicians and the optimal design of clinical stroke trials. Mechanisms of ischemic injury might differ among different stroke subtypes. Certain subtypes might be clinically identified as suboptimal for future therapeutic or prophylactic stroke trials. Some subtypes might be so clinically distinct that extensive laboratory investigation is unwarranted. Investigators in the ongoing Trial of ORG 10172 in Acute Stroke Treatment are using criteria to categorize stroke etiology among enrolled patients into one of five subtypes: large-artery atherothromboembolic, cardioembolic, small-vessel thrombotic, other etiology, or undetermined etiology. As part of the study, physicians initially predict the most likely subtype of stroke based on clinical features and baseline CT. Three months after stroke, investigators use the criteria, which also incorporate results of diagnostic testing, to reclassify stroke subtype. Initial clinical impression of subtype agreed with final determination in 62% of patients, and the rate was similar for all stroke subtypes. No stroke subtype was more accurately diagnosed than others by initial assessment. No subtype was more commonly identified by diagnostic studies. Fifteen percent of patients remained without a clear etiologic subtype diagnosis at 3 months. We conclude that clinical trials in stroke should not attempt to restrict entry into trials based on presumed stroke subtype. A careful evaluation for etiology is justified in all patients presenting with stroke, regardless of presumed subtype.

Baseline NIH Stroke Scale score strongly predicts outcome after stroke: a report of the Trial of ORG 10172 in Acute Stroke Treatment (TOAST)

July 1999


900 Reads

To compare the baseline National Institutes of Health Stroke Scale (NIHSS) score and the Trial of Org 10172 in Acute Stroke Treatment (TOAST) stroke subtype as predictors of outcomes at 7 days and 3 months after ischemic stroke. Using data collected from 1,281 patients enrolled in a clinical trial, subtype of stroke was categorized using the TOAST classification, and neurologic impairment at baseline was quantified using the NIHSS. Outcomes were assessed at 7 days and 3 months using the Barthel Index (BI) and the Glasgow Outcome Scale (GOS). An outcome was rated as excellent if the GOS score was 1 and the BI was 19 or 20 (scale of 0 to 20). Analyses were adjusted for age, sex, race, and history of previous stroke. The baseline NIHSS score strongly predicted outcome, with one additional point on the NIHSS decreasing the likelihood of excellent outcomes at 7 days by 24% and at 3 months by 17%. At 3 months, excellent outcomes were noted in 46% of patients with NIHSS scores of 7 to 10 and in 23% of patients with scores of 11 to 15. After multivariate adjustment, lacunar stroke had an odds ratio of 3.1 (95% CI, 1.5 to 6.4) for an excellent outcome at 3 months. The NIHSS score strongly predicts the likelihood of a patient's recovery after stroke. A score of > or =16 forecasts a high probability of death or severe disability whereas a score of < or =6 forecasts a good recovery. Only the TOAST subtype of lacunar stroke predicts outcomes independent of the NIHSS score.

Acute blood glucose level and outcome from ischemic stroke. Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators

February 1999


114 Reads

To study the relation between acute blood glucose level and outcome from ischemic stroke. Hyperglycemia may augment acute ischemic brain injury and increase the risk of hemorrhagic transformation of the infarct. The authors analyzed the relation between admission blood glucose level (within 24 hours from ischemic stroke onset) and clinical outcome in 1,259 patients enrolled in the Trial of ORG 10172 in Acute Stroke Treatment (TOAST)-a placebo-controlled, randomized, double-blind trial to test the efficacy of a low-molecular weight heparinoid in acute ischemic stroke. Very favorable outcome was defined as a Glasgow Outcome Scale score of 1 and a modified Barthel index of 19 or 20. Neurologic improvement at 3 months was defined as a decrease by > or =4 points on the NIH Stroke Scale compared with baseline or a final score of 0. Hemorrhagic transformation of infarct was assessed within 10 days after onset of stroke with repeat cerebral CT. Stroke subtype as lacunar or nonlacunar (atherothromboembolic, cardioembolic, and other or undetermined etiology) was classified by one investigator after completion of stroke evaluation according to study protocol. In all strokes combined (p = 0.03) and in nonlacunar strokes (p = 0.02), higher admission blood glucose levels were associated with worse outcome at 3 months according to multivariate logistic regression analysis adjusted for stroke severity, diabetes mellitus, and other vascular risks. In lacunar strokes, the relationship between acute blood glucose level and outcome was related to treatment. In the placebo group, higher admission blood glucose levels were associated with better outcome at 3 months. However, in the active drug group, as the glucose level increased from 50 to 150 mg/dL, the probability of a very favorable outcome decreased sharply and remained relatively unchanged as the glucose level increased further (p = 0.002, for overall effect of glucose on outcome). Acute blood glucose level was not associated with symptomatic hemorrhagic transformation of infarcts or with neurologic improvement at 3 months. During acute ischemic stroke hyperglycemia may worsen the clinical outcome in nonlacunar stroke, but not in lacunar stroke, and is not associated with an increased risk of hemorrhagic transformation of the infarct.

An Israeli family with Gerstmann-Sträussler-Scheinker disease manifesting the codon 102 mutation in the prion protein gene

January 1994


20 Reads

We report the first family among the Jewish population in Israel with Gerstmann-Sträussler-Scheinker disease. A proline-for-leucine substitution at the codon 102 of the prion protein (PrP) gene was demonstrated. This mutation has been reported in families with the ataxic form of the disease.

Gerstmann-Straussler-Scheinker disease with mutation at codon 102 and methionine at codon 129 of PRNP in previously unreported patients

July 1995


15 Reads

We present two patients with Gerstmann-Sträussler-Scheinker disease (GSS), one from a previously undescribed kindred and one from the Canadian branch of a previously reported British kindred. In both patients, GSS is caused by a substitution of thymine for cytosine at codon 102 of the prion protein gene (PRNP). In each patient, we confirmed the clinical diagnosis by neuropathologic examination. The mutation, causing a substitution of leucine for proline at residue 102 (P102L) of the prion protein, has been previously reported in at least 30 other families. In the patients described here, the mutation was in coupling with methionine at PRNP codon 129.

The Crow-Fukase syndrome: A study of 102 cases in Japan

July 1984


125 Reads

Clinical manifestations of 102 cases with the Crow- Fukase syndrome (the syndrome of polyneuropathy, anasarca, skin changes, endocrinopathy, dysglobulinemia, and organomegaly), with or without myeloma, were reviewed. Fifty-six cases with myeloma consisted of 31 with osteosclerotic, 17 with mixed osteosclerotic and osteolytic, and 8 with osteolytic. Forty-six cases without myeloma consisted of 2 with extramedullary plasmacytoma, 33 with M protein alone, and 11 with polyclonal protein alone. There was no significant difference in incidence of the major clinical manifestations between the two groups with and without myeloma. They had a common characteristic histologic finding of the lymph node resembling that of Castleman's disease.

A phase I trial of solubilized DR2:MBP84-102 (AG284) in multiple sclerosis

May 2000


68 Reads

To assess the safety, tolerability, and biologic and clinical activity of a solubilized complex comprised of human leukocyte antigen-DR2 with myelin basic protein84-102 (AG284)in patients with secondary progressive MS. Soluble species-specific major histocompatibility complex myelin basic protein91-103 complexes ameliorate disease in a dose-dependent manner when administered to SJL/J mice with chronic relapsing experimental allergic encephalomyelitis. Preincubation with AG284 reduces the proliferative response of a DR2-restricted, myelin basic protein84-102-reactive T cell clone, derived from a MS patient, to myelin basic protein84-102 in the presence of autologous antigen-presenting cells. Thirty-three patients with secondary progressive MS were randomly assigned to receive three alternate day IV doses of AG284 or placebo in a double-masked dose escalation study. The primary outcome was safety and tolerability. Secondary outcomes included a comparison of pre- and post-treatment gadolinium-enhanced brain MRI activity, Kurtzke Expanded Disability Status Scale, and Nine Hole Peg Test scores. The frequency of adverse events was similar in the AG284 and placebo recipients. No significant treatment effect was detected by Expanded Disability Status Scale, Nine Hole Peg Test, or number of new gadolinium-enhancing MRI lesions. AG284 as administered during this study was safe and well tolerated. Further studies are warranted to determine the biologic activity and clinical efficacy of this potential treatment for MS.

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