[show abstract][hide abstract] ABSTRACT: A 2003 evidence-based review of exogenous risk factors for sporadic amyotrophic lateral sclerosis (ALS) identified smoking as the only risk factor that attained "probable" (more likely than not) status, based on 2 class II studies. The purpose of the current, evidence-based, update was to see if the conclusion of the previous review needed to be modified, based on studies published since.
A Medline literature search was conducted for the period between 2003 and April 2009 using the search terms smoking and (ALS or "amyotrophic lateral sclerosis" or MND or "motor neuron disease"). The references of primary articles and reviews were checked to assure completeness of the search. Primary articles published since the previous review were classified as before.
Twenty-eight titles were identified, but only 7 articles met inclusion criteria. Of these, 1 provided class II evidence, and 1 class III evidence: both showed increased risk of ALS with smoking. The class II study showed a dose-response effect, and risk decreasing with number of years since quitting smoking. Five articles provided class IV or V evidence, which may not be relied upon to draw conclusions.
Smoking may be considered an established risk factor for sporadic amyotrophic lateral sclerosis (ALS) (level A rating; 3 class II studies, 1 class III study). Evidence-based analysis of epidemiologic data shows concordance among results of better-designed studies linking smoking to ALS, and lets those results drive the conclusions.
[show abstract][hide abstract] ABSTRACT: OBJECTIVE: To determine, when, how, and which neurons initiate the onset of pathophysiology in amyotrophic lateral sclerosis (ALS) using a transgenic mutant sod1 zebrafish model and identify neuroprotective drugs. METHODS: Proteinopathies such as ALS involve mutant proteins that misfold and activate the heat shock stress response (HSR). The HSR is indicative of neuronal stress, and we used a fluorescent hsp70-DsRed reporter in our transgenic zebrafish to track neuronal stress and to measure functional changes in neurons and muscle over the course of the disease. RESULTS: We show that mutant sod1 fish first exhibited the HSR in glycinergic interneurons at 24 hours postfertilization (hpf). By 96 hpf, we observed a significant reduction in spontaneous glycinergic currents induced in spinal motor neurons. The loss of inhibition was followed by increased stress in the motor neurons of symptomatic adults and concurrent morphological changes at the neuromuscular junction (NMJ) indicative of denervation. Riluzole, the only approved ALS drug and apomorphine, an NRF2 activator, reduced the observed early neuronal stress response. INTERPRETATION: The earliest event in the pathophysiology of ALS in the mutant sod1 zebrafish model involves neuronal stress in inhibitory interneurons, resulting from mutant Sod1 expression. This is followed by a reduction in inhibitory input to motor neurons. The loss of inhibitory input may contribute to the later development of neuronal stress in motor neurons and concurrent inability to maintain the NMJ. Riluzole, the approved drug for use in ALS, modulates neuronal stress in interneurons, indicating a novel mechanism of riluzole action. ANN NEUROL 2011.
Annals of Neurology 10/2012; · 11.19 Impact Factor
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