Pathologic laughter and crying in ALS: a search for their origin

Spells of laughter and crying are well known in patients with amyotrophic lateral sclerosis (ALS). Since ALS occurs mostly in older age groups, this brings up the possibility that aging changes in the brain could play a causative role in the origin of such spells. To rule out or at least reduce the complicating factor of aging, a study was made of the incidence of pathologic laughter and crying in patients whose motor neuron disease had started before the age of 45 years. The data were collected from 73 such individuals, all with confirmed ALS. All told, 36 had experienced episodes of pathologic laughter and/or crying. Of these, 20 had bouts of both laughter and crying. 9 bouts of crying alone and 7 spells of laughter alone. Nearly all with such emotional spells had developed bulbar involvement with the illness. The youngest patient with spells was 31 when his illness began and 35 when he started to have bouts of crying.     

Statistical MUNE: A comparison of two methods of setting recording windows in healthy subjects and ALS patients

OBJECTIVE: To address the issue as to how best to perform statistical MUNE, we applied two different approaches and compared results in healthy subjects and ALS patients. METHODS: Twelve normal subjects (women 8, mean age 52years) and 11 ALS patients (women 4, mean age 54years) underwent two consecutive MUNE studies, which differed in terms of setting and modifying the recording window. These are referred to as the 'expansion' and 'narrowing' methods, respectively. Size-weighted average (Av) SMUP and MUNE values were obtained using the two methods, and compared in control and patient groups. RESULTS: Expansion method-derived Av SMUP sizes and MUNE values differed only slightly from those obtained using the narrowing method in healthy subjects, whereas the narrowing method resulted in significantly larger Av SMUP sizes and smaller MUNE values than the expansion method in ALS patients (Wilcoxon signed ranks test, p=0.003). The sizes of tested areas (mean+/-SD) were significantly larger for the narrowing method than the expansion method in both subject groups with much greater difference in ALS patients; 9.6+/-3.1% vs. 7.9+/-1.7% in healthy subjects and 16.1+/-5.1% vs. 11.2+/-3.0% in ALS patients (Student t-test, p<0.01). CONCLUSIONS: The present study shows, unlike that found in normal subjects, that the results of statistical MUNE in ALS patients are heavily dependent on the approach used to set and modify recording windows. SIGNIFICANCE: The expansion method using a 10%-sized window is likely to suffer from systemic errors due to the ceiling effect and the sampling of artifactually small motor units in ALS patients. The authors recommend that the narrowing method be considered as an alternative that avoids these problems.     

Serum Levels of Free Insulin-Like Growth Factor (IGF)-I in Normal Children

Serum levels of free insulin-like growth factor (IGF)-I were measured by immunoradiometric assay (IRMA) in fasting sera of 137 normal boys and 120 normal girls aged from 8 to 15 yr to study relationships between free IGF-I levels and ages, total IGF-I, IGF binding protein (IGFBP)-1, IGFBP-3, and acid-labile subunit (ALS) levels. In both sexes, serum free IGF-I levels and the ratios of free IGF-I to total IGF-I were significantly higher in the pubertal age groups than in the prepubertal age groups. Serum levels of free IGF-I showed a significant positive correlation with those of total IGF-I, IGFBP-3 and ALS, while they showed a significant negative correlation with those of IGFBP-1. These observations suggest that increase in serum free IGF-I levels during puberty is caused by a dramatic increase in total IGF-I, rather than IGFBP-3, and a decrease in IGFBP-1. Also, high free IGF-I levels may play an important role in pubertal growth spurt.     

Characterization of three different human T cell membrane antigens,two being present on T lymphocyte subpopulations

Heteroantisera were raised in rabbits to thymocytes, HSB2 cells, and Sezary cells. Following absorption with Ia-positive leukemia cells, these sera appeared to be specific for different T cell antigens. Both the anti-HSB2 and the anti-Sezary sera reacted with approximately 50% and the antihymocyte serum with 100% of normal peripheral blood T lymphocytes. None of the sera reacted with B cells. The apparent molecular weights of the antigens being derected were determined by immunoprecipitation followed by SDS polyacrylamide gel eletrophoresis. A dimer of 170,000 daltons consisting of two similar 85,000-dalton polypeptide chains was immunoprecipitated by the anti-HSB2 serum whereas single polypeptides of 53,000 and 64,000 daltons were immunoprecipitated by the anti-Sezary and antithymocyte sera, respectively.     

Divergent effects of prostaglandin receptor signaling on neuronal survival

Induction of cyclooxygenase-2 (COX-2) with production of prostaglandins occurs in a wide spectrum of acute and chronic neurodegenerative diseases and is associated with neuronal death. Inhibition of the COX-2 pathway and downstream production of prostaglandins protect neurons in rodent models of cerebral ischemia and neurodegeneration. Recent studies investigating the functions of selected prostaglandin receptor pathways in mediating COX-2 neurotoxicity have demonstrated both toxic and paradoxically neuroprotective effects of several receptors in models of excitotoxicity. In this study, we investigate the functions of additional prostaglandin receptors not previously characterized in organotypic models of glutamate excitotoxicity. We find that PGD₂, PGI₂, and PGF_2α receptors protect motor neurons in an organotypic spinal cord model of amyotrophic lateral sclerosis (ALS). In addition, PGI₂ and TXA₂ receptors rescue CA1 neurons in an organotypic hippocampal model of N-methyl-d-aspartate excitotoxicity. However, in a model of inflammation induced by lipopolysaccharide, prostaglandin receptors previously found to be protective in excitotoxicity now cause CA1 neuronal death. Taken together, these studies identify novel eicosanoid receptor signaling pathways that mediate neuronal protection in excitotoxic paradigms; these data also support the emerging hypothesis that the toxic/protective effects of eicosanoid signaling on neuronal viability diverge significantly depending on whether excitotoxicity or inflammation predominates as the underlying toxic stimulus.     

Titration of Mechanical Insufflation–Exsufflation Optimal Pressure Combinations in Neuromuscular Diseases by Flow/Pressure Waveform Analysis

IntroductionThe aim of this study was to assess several air-pressure settings for MI–E to determine their effect on peak cough flow (PCF), and to compare the best pressures with those are more common used in the literature (±40 cmH₂O) in patients with neuromuscular disorders (NMD).MethodsAdults with NMD in whom MI–E was indicated were recruited. Assisted PCF was measured by an external pneumotachograph. The protocol included 9 PCF measures per patient: 1 baseline (non-assisted), 4 with increasing inspiratory pressures without negative pressure (10, 20, 30 and 40 cmH₂O or maximum tolerated), and then 4 adding expiratory pressures (?10, ?20, ?30 and ?40 cmH₂O or maximum tolerated) with maximum inspiratory pressure previously achieved.ResultsTwenty one patients were included, 61% with amyotrophic lateral sclerosis (ALS). Mean PCFs with recommended pressures (±40 cmH₂O) were lower than the scored in the individualized steps of the titration protocol (197.7 ± 67 l/min vs 214.2 ± 60 l/min, p < 0.05). Regarding subgroups, mean PCF_max values in ALS patients with bulbar symptoms were significantly higher than those achieved with recommended pressures (163.6 ± 80 vs 189 ± 66 l/min, p < 0.05).ConclusionThe PCF_max obtained with the protocol did not always match the recommended settings. It may be advisable to perform MI–E titration assessed by non-invasive PCF monitoring in patients with NMD, especially in ALS with bulbar involvement to improve the therapy detecting airway collapse induced by high pressures.     

Arimoclomol: a potential therapy under development for ALS

Arimoclomol, an amplifier of heat shock protein expression involved in cellular stress response, has emerged as a potential therapeutic candidate in amyotrophic lateral sclerosis (ALS) in recent years. Treatment with arimoclomol was reported to improve survival and muscle function in a mouse model of motor neuron disease. Several single- and multiple-dose safety studies have been completed in healthy control subjects. A 3-month Phase IIa study in people with ALS demonstrated safety at dosages up to 300 mg/day and another study is currently recruiting participants with familial ALS caused by mutations in the superoxide dismutase gene. We review the rationale for testing arimoclomol in sporadic and familial ALS in the context of available safety and pharmacokinetic data. Published and unpublished literature relative to the drug in the past two decades is discussed. The current review attempts to bring together our existing understanding of the actions of arimoclomol with the disease profile of ALS. The pharmacological profile of arimoclomol and the available preclinical data make it a promising therapeutic possibility in ALS.