Phase-locking of magnetic islands diagnosed by ECE-imaging.

Millimeter-wave imaging diagnostics identify phase-locking and the satisfaction of 3-wave coupling selection criteria among multiple magnetic island chains by providing a localized, internal measurement of the 2D power spectral density, S(ω, kpol). In high-confinement tokamak discharges, these interactions impact both plasma rotation and tearing stability. Nonlinear coupling among neoclassical tearing modes of different n-number, with islands not satisfying the poloidal mode number selection criterion ⟨m, m('), m - m(')⟩, contributes to a reduction in core rotation and flow shear in the vicinity of the modes.

Lead exposure as a risk factor for amyotrophic lateral sclerosis.

BACKGROUND: The etiology of amyotrophic lateral sclerosis (ALS) likely involves an environmental component. We qualitatively assessed literature on ALS and lead exposure. Problems of study design make case reports and studies of lead in blood or tissues difficult to interpret. Most previous case-control studies found an association of ALS with self-reported occupational exposure to lead, with increased risks of 2- to >4-fold. However, these results may have been affected by recall bias. OBJECTIVE: To address inconsistencies among published reports, we used both lead biomarkers and interview data to assess lead exposure, and we evaluated the role of genetic susceptibility to lead. METHODS: We conducted a case-control study in New England in 1993-1996 with 109 ALS cases and 256 population-based controls. We measured blood and bone lead levels, the latter using X-ray fluorescence, and interviewed participants regarding sources of lead exposure. RESULTS: In our study, ALS was associated with self-reported occupational lead exposure, with a dose response for cumulative days of exposure. ALS was also associated with blood and bone lead levels, with a 1.9-fold increase in risk for each mug/dl increment in blood lead and a 2.3- to 3.6-fold increase for each doubling of bone lead. A polymorphism in the delta-aminolevulinic acid dehydratase gene was associated with a 1.9-fold increase in ALS risk. CONCLUSION: These results, together with previous studies, suggest that lead exposure plays a role in the etiology of ALS. An increase in mobilization of lead from bone into blood may play a role in the acute onset of disease.

Slowing down ALS--is this good or bad?

The availability of a drug that provides modest relief in ALS without altering its inevitable progression and end, has posed new ethical and economic problems for patients, caregivers and physicians. Early evidence suggests that riluzole does provide a short additional quality of life and economic benefit for patient and society. However, there is a clear need for additional therapies, even if the benefit is minor.

Serum insulin-like growth factor-I (IGF-I) does not correlate positively with isometric strength, fatigue, and quality of life in post-polio syndrome.

OBJECTIVES AND BACKGROUND: To determine if serum insulin-like growth factor-I (IGF-I) levels are associated with strength, body mass index (BMI), fatigue, or quality of life in post-poliomyelitis syndrome (PPS). PPS is likely due to a distal disintegration of enlarged post-polio motor units as a result of terminal axonal sprouting. Age-related decline in growth hormone and IGF-I (which support terminal axonal sprouts) is proposed as a contributing factor. METHODS: As part of the North American Post-Poliomyelitis Pyridostigmine Study (NAPPS), baseline data on maximum voluntary isometric contraction (MVIC), BMI, subjective fatigue (fatigue severity scale, Hare fatigue symptom scale), health-related quality of life (short form health survey-36; SF-36), and serum IGF-I levels were gathered on 112 PPS patients. Pearson correlation coefficients were calculated to evaluate the association between serum IGF-I and MVIC in 12 muscles, BMI, two fatigue scales, and SF-36 scale scores. RESULTS: There is a significant inverse correlation of IGF-I levels with MVIC in left ankle dorsiflexors (r=-0.30, P<0.01), and left and right knee extensors (r=-0.22, -0.25, P=<0.01, 0.01), but no significant correlations in other muscles. When men and women were evaluated separately, inverse correlations of IGF-I levels with MVIC were found only in men. IGF-I correlated inversely with BMI (r=-0.32, P=0006) and age (r=-0.32, P=0.0005). IGF-I did not correlate with the fatigue or SF-36 scales. CONCLUSIONS: In this exploratory study, we found that contrary to our expectations, IGF-I did not correlate positively with strength. IGF-I correlated negatively with strength in several lower extremity muscles, BMI, and age. IGF-I is likely not an important factor in the pathogenesis of fatigue and in determining quality of life in PPS, but its role on strength should be studied further.

Dietary intake of calcium, magnesium and antioxidants in relation to risk of amyotrophic lateral sclerosis.

Dietary factors have long been suspected of being risk factors for amyotrophic lateral sclerosis (ALS), but few human studies have been reported. To address several of the dietary hypotheses, a case-control study of risk factors for ALS conducted in New England in 1993-1996 included an abbreviated food frequency questionnaire. We examined the dietary intake of calcium, magnesium and antioxidants among 107 ALS cases and 262 community controls. Overall, these dietary factors were not related to risk of ALS, though modestly protective associations were suggested for magnesium and lycopene.

The global burden of disease study: implications for neurology.

Because of the epidemiological transition, the global burden of illness has changed. Several factors have contributed to this change, including improvements in maternal and child health, increasing age of populations, and newly recognized disorders of the nervous system. It is now evident that neurologic disorders have emerged as priority health problems worldwide. This is reflected in the Global Burden of Disease Study, jointly published by the World Health Organization and other groups. The proportionate share of the total global burden of disease resulting from neuropsychiatric disorders is projected to rise to 14.7% by 2020. Although neurologic and psychiatric disorders comprise only 1.4% of all deaths, they account for a remarkable 28% of all years of life lived with a disability. This study provides compelling evidence that one cannot assess the neurologic health status of a population by examining mortality statistics alone. Health ministries worldwide must prioritize neurologic disorders, and neurologists must be prepared to provide care for increased numbers of people individually and in population groups.

The ALS patient care database: goals, design, and early results. ALS C.A.R.E. Study Group.

OBJECTIVE: The ALS Patient Care Database was created to improve the quality of care for patients with ALS by 1) providing neurologists with data to evaluate and improve their practices, 2) publishing data on temporal trends in the care of patients with ALS, and 3) developing hypotheses to be tested during formal clinical trials. BACKGROUND: Substantial variations exist in managing ALS, but there has been no North American database to measure outcomes in ALS until now. METHODS: This observational database is open to all neurologists practicing in North America, who are encouraged to enroll both incident and prevalent ALS patients. Longitudinal data are collected at intervals of 3 to 6 months by using standard data collection instruments. Forms are submitted to a central data coordinating center, which mails quarterly reports to participating neurologists. RESULTS: Beginning in September 1996 through November 30, 1998, 1,857 patients were enrolled at 83 clinical sites. On enrollment, patients had a mean age of 58.6 years +/-12.9 (SD) years (range, 20.1 to 95.1 years), 92% were white, and 61% were men. The mean interval between onset of symptoms and diagnosis was 1.2+/-1.6 years (range, 0 to 31.9 years). Riluzole was the most frequently used disease-specific therapy (48%). Physical therapy was the most common nonpharmacologic intervention (45%). The primary caregiver was generally the spouse (77%). Advance directives were in place at the time of death for 70% of 213 enrolled patients who were reported to have died. CONCLUSIONS: The ALS Patient Care Database appears to provide valuable data on physician practices and patient-focused outcomes in ALS.

Consensus guidelines for the design and implementation of clinical trials in ALS. World Federation of Neurology committee on Research.

BACKGROUND: In 1994 consensus guidelines were developed for conducting clinical trials in ALS. With growing experience in clinical trials, it has become clear that a number of further guidelines were needed. METHODS: Under the auspices of the World Federation of Neurology Committee on Research, a multinational group of neurologists, statisticians, patient advocates, representatives from the pharmaceutical industry as well as regulatory agencies developed consensus about a number of revisions to the existing guidelines during a 2 day conference in April 1998. RESULTS: Expanded areas of focus include greater protection of patient rights, more detailed guidelines for outcome measures statistical analyses, disclosure of study results and improved interaction between investigators and the corporate sector. COMMENT: Substantial progress has been made in standardizing and improving the quality of clinical trials in ALS through these consensus guidelines.

A multicenter, randomized, double-blinded trial of pyridostigmine in postpolio syndrome.

BACKGROUND: Postpoliomyelitis syndrome (PPS) is likely due to degeneration and dysfunction of terminal axons of enlarged postpolio motor units. Age-related decline in growth hormone and insulin-like growth factor (IGF-I) may be a contributing factor. Neuromuscular junction abnormalities and decreased IGF-I levels may respond to the anticholinesterase pyridostigmine, with consequent improvement in strength, fatigue, and quality of life. OBJECTIVES: To determine the effect of pyridostigmine in PPS on health-related quality of life, isometric muscle strength, fatigue, and serum IGF-I levels; and to assess the safety of pyridostigmine in PPS. METHODS: The study was a multicenter, randomized, double-blinded, placebo-controlled trial of a 6-month course of pyridostigmine 60 mg three times per day in 126 PPS patients. The primary data analysis compared mean changes of outcomes between treatment and control groups at 6 months using an intention to treat approach. Secondary analyses included a comparison of outcomes at 6 and 10 weeks, and in compliant patients. RESULTS: The study showed no significant differences in pyridostigmine and placebo-treated patients with regard to changes in quality of life, isometric strength, fatigue, and IGF-I serum levels at 6 months in the primary analysis and in compliant patients. There were no differences in outcomes at 6 and 10 weeks between groups. However, very weak muscles (1 to 25% predicted normal at baseline) were somewhat stronger (p = 0.10, 95% CI of difference -9.5 to 73.3%), and in compliant patients IGF-I was somewhat increased (p = 0.15, 95% CI of difference -6.4 to 44.8 ng/mL) at 6 months with the medication. Pyridostigmine was generally well tolerated. CONCLUSIONS: This study showed no significant differences between pyridostigmine and placebo-treated PPS patients on measures of quality of life, isometric strength, fatigue, and serum IGF-I.

The relationship of lower-limb muscle force to walking ability in patients with amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: The purpose of this study was to determine the level of muscle force associated with ability to walk in the community without assistance, in the community with assistance, or at home only in individuals with amyotrophic lateral sclerosis (ALS). SUBJECTS AND METHODS: Percentage of predicted maximal muscle force (%PMF) of lower-extremity muscles was determined, and walking ability was categorized in 118 patients with ALS during periodic visits to the Neuromuscular Research Unit. Data were derived from consecutive visits in which subjects demonstrated declines in walking ability. Means for %PMF of each muscle group and a limb average were calculated at each consecutive visit. RESULTS: The mean lower-extremity average %PMF was: (1) 54.01% (SD=12.76%) for subjects who walked independently in the community and 50.19% (SD=14.38%) during the next visit when these same subjects required assistance in the community (difference=3.82%, 95% confidence interval [CI]= 2.45-5.19);(2) 37.52% (SD=15.17%) during the last visit that subjects walked with assistance in the community and 32.18% (SD=13.83%) during the next visit when they walked only at home (difference=5.33%, 95% CI=3.61-7.06); and (3) 19.12% (SD=9.08%) during the visit when subjects were last able to ambulate at home versus 13.70% (SD=7.36%) when they became unable to walk (difference=5.42%, 95% CI=2.97-7.96). CONCLUSION AND DISCUSSION: The findings suggest there are required levels of lower-extremity muscle force for various categories of walking ability. Variations in forces within and between categories of walking ability, however, indicate the complexity of this relationship.

Association of cigarette smoking with amyotrophic lateral sclerosis.

We explored the relationship between amyotrophic lateral sclerosis (ALS) and cigarette smoking in a case-control study conducted in New England from 1993 to 1996. Recently diagnosed ALS cases (n = 109) were recruited from two major referral centers. Population controls (n = 256) were identified by random telephone screening. Data were analyzed by logistic regression. After adjusting for age, sex, region and education, ever having smoked cigarettes was associated with an increase in risk for ALS (odds ratio 1.7; 95% confidence interval 1.0-2.8). Average cigarettes smoked per day, years smoked and pack-years were all greater in cases than controls, but dose-response trends were not observed. Similar numbers of cases and controls had ever used alcohol, and only a small, nonsignificant association of drinks per month with ALS was observed. The association of cigarette smoking with ALS was not affected by adjusting for alcohol use. In contrast, the weak relationship of ALS with alcohol use was apparently due to confounding by smoking.

Pilot study of myoblast transfer in the treatment of Becker muscular dystrophy.

We evaluated myoblast implantation therapy in three subjects with Becker muscular dystrophy who received 60 million myoblasts in one tibialis anterior (TA) muscle 2 months after beginning cyclosporine immunosuppression (5 to 10 mg/kg) that continued for 1 year. Strength of the implanted and control TA muscles was measured before and after treatment using a gauge to record TA contraction force. Our protocol controlled for the effects of cyclosporine and myoblast injections. In this pilot study, myoblast implantation did not improve strength of the implanted TA muscles.

Lower extremity muscle force measures and functional ambulation in patients with amyotrophic lateral sclerosis.

OBJECTIVE: To examine the relation between lower extremity muscle force production and functional ambulation in patients with amyotrophic lateral sclerosis (ALS). DESIGN: Retrospective analysis of data collected from 1979 to 1995. PATIENTS: Two hundred forty ALS patients referred to the New England Medical Center Neuromuscular Research Unit. MAIN OUTCOME MEASURES: Muscle force production during a maximum, voluntary isometric contraction of ankle dorsiflexors, knee flexors, knee extensors, hip flexors, and hip extensors was calculated as percent predicted maximal force (PPMF). Functional ambulation status was classified as unable, home, or community. RESULTS: The probability of community ambulation compared with home increased with progressively higher PPMF for all muscle groups. Subjects with knee flexion strength greater than 75% PPMF were 395 times more likely to ambulate in the community. Subjects with hip extension strength over 50% PPMF showed improved chance of ambulation at home. CONCLUSION: Lower extremity PPMF is a critical factor determining functional ambulation in patients with ALS. Knee flexors play an important role in community ambulation while the hip extensors are important for home ambulation.

Mutations in the glutamate transporter EAAT2 gene do not cause abnormal EAAT2 transcripts in amyotrophic lateral sclerosis.

Recently, variant mRNA transcripts for the astroglial glutamate transporter EAAT2 have been detected in brain tissues of 60% of patients with sporadic amyotrophic lateral sclerosis (SALS). We have tested the hypothesis that the gene for EAAT2 may be defective in some ALS cases. In 16 familial ALS (FALS) pedigrees without mutations in SOD1, we failed to detect genetic linkage to the EAAT2 locus. We next characterized the genomic organization of the EAAT2 gene and used single-strand conformation polymorphism analysis of genomic DNA to identify one novel mutation in a single SALS patient and two novel mutations in 2 affected FALS siblings. In the SALS patient, the mutation substitutes serine for an asparagine that might be involved in N-linked glycosylation of the EAAT2 protein. In the 2 affected individuals in the FALS family, we detected both a mutation in the 5' end of intron 7 and a silent G --> A transition at codon 234 in exon 5. It remains unclear whether this intron 7 mutation is related to the defective mRNA splicing. These studies indicate that germline mutations in the EAAT2 gene are infrequent and do not explain the presence of variant mRNA transcripts of EAAT2 in more than one-half of ALS cases.

Intrathecal administration of recombinant human superoxide dismutase 1 in amyotrophic lateral sclerosis: a preliminary safety and pharmacokinetic study.

We undertook a safety and pharmacokinetic study of intrathecal (i.t.) recombinant human superoxide dismutase (rhSOD1). We administered rhSOD1 as an acute bolus in three sheep and 16 human subjects with amyotrophic lateral sclerosis (ALS). Two sheep received chronic i.t. infusion of rhSOD1 (one at 17.7 mg per day, the second at 38.0 mg per day) for six months. Two of the 16 subjects had familial ALS and mutations in the gene for Cu/Zn SOD1. They both received i.t. infusion of rhSOD1 (5 to 10 mg per day) for 3 to 6 months. Intrathecal rhSOD1 administration was safe. Bolus i.t. administration of 0.25 mg rhSOD1 in sheep revealed a mean elimination half-life of 0.4 (SD +/- 0.06) hours, clearance of 12.2 +/- 3.2 ml per hour, and volume of distribution of 7.3 +/- 0.9 ml. After chronic i.t. infusion, the initial alpha-phase half-life was estimated as 1.2 hours and the extended beta-phase half-life was 15.0 hours. The mean clearance rate was 25.9 ml per hour and the steady-state volume of distribution was 920.6 ml. Bolus i.t. administration of 20 micrograms of rhSOD1 in ALS subjects revealed a mean elimination half-life of 2.2 +/- 0.8 hours, clearance of 1.2 +/- 0.6 ml per hour, and volume of distribution of 3.5 +/- 0.4 ml. With chronic i.t. infusion of 5 mg per day, cerebrospinal SOD1 levels increased approximately fortyfold. We detected no benefit of this treatment in the two patients with familial ALS.

Effect of increased maxillo-mandibular relationship on isometric strength in TMD patients with loss of vertical dimension of occlusion.

The effect on isometric strength of the shoulders and limbs while biting in habitual occlusion, on a bite-elevating appliance and on a placebo appliance was analyzed. Twenty female volunteer patients, presenting with temporomandibular pain dysfunction syndrome and obvious loss of vertical dimension, served as subjects. All were weaker to the manual application of the isometric Deltoid Press (IDP) when biting, as opposed to maintaining the mandible in an unsupported rest position. Two intraoral appliances were fabricated for each subject: a bite-elevating appliance (BEA) set by a functional criterion of peak strength to the IDP and a placebo appliance which did not interfere with occlusion but was "set" with a mock IDP procedure. Testing was carried out by the Neuromuscular Research Testing Laboratory of the Neurology Department of Tufts New England Medical Center. Testing was independent of the dentist who fabricated and set the appliances. A standard neuromuscular test with the Maximal Voluntary Isometric Contraction apparatus was used to assess strength of right and left shoulder, elbow and knee flexion and extension as is routinely performed with all neuromuscular disease patients. Twelve strength tests were carried out for each of three conditions: 1. Baseline-biting in habitual occlusion; 2. Elevated-biting on the BEA; and 3. Placebo-biting with the placebo appliance inserted. The order of conditions 2 and 3 was counterbalanced without knowledge of the subjects. Twelve repeated measures ANOVAs (each subject as their own control) were conducted for each of the 12 strength measures. All F-tests indicated a significant main effect for treatment differences (p < 0.0001). Mean strength biting on the BEA was consistantly greater (p < 0.001) than Baseline or Placebo strength. Baseline and Placebo condition were equivalent. These findings confirmed previous observations at this TMD Center: individuals with loss of vertical dimension of occlusion respond to a bite raising appliance by increased isometric-strength.

Toxicity and tolerability of recombinant human ciliary neurotrophic factor in patients with amyotrophic lateral sclerosis.

We examined the toxicity of both single and multiple subcutaneous injections of recombinant human ciliary neurotrophic factor (rhCNTF) in 72 patients with ALS, in doses ranging from 2 to 100 micrograms/kg. Adverse events were generally dose related and ranged from mild to severe. The tolerability of daily subcutaneous rhCNTF was equivalent to placebo at doses < or = 5 micrograms/kg/day. At higher doses, anorexia, weight loss, reactivation of herpes simplex virus (HSV1) labialis/stomatitis, cough, and increased oral secretions occurred.