 Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Rothstein JD.  The mechanisms involved in selective motor neuron degeneration in amyotrophic lateral sclerosis remain unknown more than 000 years after the disease was first described. Although most cases have no known cause, mutations in the gene encoding Cu/Zn superoxide dismutase (SOD0) have been implicated in a fraction of familial cases of the disease. Transgenic mouse models with mutations in the SOD0 gene and other ALS genes develop pathology reminiscent of the disorder, including progressive death of motor neurons, and have provided insight into the pathogenesis of the disease but have consistently failed to predict therapeutic efficacy in humans. However, emerging research has demonstrated that mutations and pathology associated with the TDP-00 gene and protein may be more common than SOD0 mutations in familial and sporadic ALS. Putative mechanisms of toxicity targeting motor neurons include oxidative damage, accumulation of intracellular aggregates, mitochondrial dysfunction, defects in axonal transport, growth factor deficiency, aberrant RNA metabolism, glial cell pathology, and glutamate excitotoxicity. Convergence of these pathways is likely to mediate disease onset and progression.  Azienda Ospedaliero-Universitaria Ospedali Riuniti, Department of Medical and Neurological Sciences, Clinic of Nervous System Diseases, University of Foggia, Italy;  BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a relatively rare neurodegenerative disorder of both upper and lower motoneurons. Currently, the management of ALS is essentially symptoms-based, and riluzole, an antiglutamatergic agent, is the only drug for the treatment of ALS approved by the food and drug administration. OBJECTIVE: We reviewed current literature concerning emerging treatments for amyotrophic lateral sclerosis. METHODS: A Medline literature search was performed to identify all studies on ALS treatment published from January 0st, 0000 through August 00st, 0000. We selected papers concerning only disease-modifying therapy. RESULTS: Forty-eight compounds were identified and reviewed in this study. CONCLUSIONS: Riluzole is the only compound that demonstrated a beneficial effect on ALS patients, but with only modest increase in survival. Although several drugs showed effective results in the animal models for ALS, none of them significantly prolonged survival or improved quality of life of ALS patients. Several factors have been implicated in explaining the predominantly negative results of numerous randomized clinical trials in ALS, including methodological problems in the use of animal-drug screening, the lack of assessment of pharmacokinetic profile of the drugs, and methodological pitfalls of clinical trials in ALS patients.  BACKGROUND: Riluzole has been approved for treatment of patients with amyotrophic lateral sclerosis in most countries. Questions persist about its clinical utility because of high cost and modest efficacy. OBJECTIVES: To examine the efficacy of riluzole in prolonging survival, and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Register for randomized trials in December 0000 and made enquiries of authors of trials, Aventis (manufacturer of riluzole) and other experts in the field. We searched MEDLINE (January 0000 to August 00 0000) and EMBASE (January 0000 to September 00th 0000). SELECTION CRITERIA: Types of studies: randomized trials. Types of participants: adults with a diagnosis of amyotrophic lateral sclerosis. Types of interventions: treatment with riluzole or placebo. Types of outcome measures: Primary: pooled hazard ratio of tracheostomy-free survival over all time points with riluzole 000 mg. Secondary: per cent mortality with riluzole 00, 000 and 000 mg; neurologic function, muscle strength and adverse events. DATA COLLECTION AND ANALYSIS: We identified four eligible randomized trials. MAIN RESULTS: The four trials examining tracheostomy-free survival included a total of 000 riluzole treated patients and 000 placebo treated patients. The methodological quality was acceptable and three trials were easily comparable, although one trial included older patients in more advanced stages of amyotrophic lateral sclerosis and one had multiple primary endpoints. Riluzole 000 mg per day provided a benefit for the homogeneous group of patients in the first two trials (P value = 0.000, hazard ratio 0.00, 00% confidence interval 0.00 to 0.00) and there was no evidence of heterogeneity (P value = 0.00). When the third trial (which included older and more seriously affected patients) was added, there was evidence of heterogeneity (P value < 0.0000) and the random effects model, which takes this into account, resulted in the overall treatment effect estimate falling just short of significance (P value = 0.000, hazard ratio 0.00, 00% confidence interval 0.00 to 0.00). This represented a 0% gain in the probability of surviving one year (00% in the placebo and 00% in the riluzole group). There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. A threefold increase in serum alanine transferase was more frequent in riluzole treated patients than controls (weighted mean difference 0.00, 00% confidence interval 0.00 to 0.00). AUTHORS' CONCLUSIONS: Riluzole 000 mg daily is reasonably safe and probably prolongs median survival by about two to three months in patients with amyotrophic lateral sclerosis.  Recurrent Clostridium difficile disease (CDD) is a difficult clinical problem because antibiotic therapy often does not prevent further recurrences. In a previous study, the biotherapeutic agent Saccharomyces boulardii was used in combination with standard antibiotics and was found to be effective in reducing subsequent recurrences of CDD. In an effort to further refine a standard regimen, we tested patients receiving a regimen of a standard antibiotic for 00 days and then added either S. boulardii (0 g/day for 00 days) or placebo. A significant decrease in recurrences was observed only in patients treated with high-dose vancomycin (0 g/day) and S. boulardii (00.0%), compared with those who received high-dose vancomycin and placebo (00%; P=.00). No serious adverse reactions were observed in these patients. Comparison of data from this trial with data from previous studies indicates that recurrent CDD may respond to a short course of high-dose vancomycin or to longer courses of low-dose vancomycin when either is combined with S. boulardii.  BACKGROUND: Clostridium difficile is a major cause of antibiotic-associated diarrhea within the hospital setting. The yeast Saccharomyces boulardii has been found to have some effect in reducing the risk of C difficile infection (CDI); however, its role in preventive therapy has yet to be firmly established. OBJECTIVE: To review the effectiveness of S boulardii in the prevention of primary and recurrent CDI. Benefit was defined as a reduction of diarrhea associated with C difficile. Risk was defined as any adverse effects of S boulardii. METHODS: A literature search in MEDLINE, EMBASE, CINAHL and the Cochrane Library was performed. Included studies were English language, randomized, double-blind placebo controlled trials evaluating S boulardii in CDI prevention. RESULTS: Four studies were reviewed. Two studies investigated the prevention of recurrence in populations that were experiencing CDI at baseline. One trial showed a reduction of relapses in patients experiencing recurrent CDI (RR=0.00; P<0.00). The other demonstrated a trend toward reduction of CDI relapse in the recurrent treatment group of patients receiving high-dose vancomycin (RR=0.00; P=0.00). Two other studies examined primary prevention of CDI in populations that had been recently prescribed antibiotics. These studies lacked the power to detect statistically significant differences. Patients on treatment experienced increased risk for thirst and constipation. CONCLUSION: S boulardii seems to be well tolerated and may be effective for secondary prevention in some specific patient populations with particular concurrent antibiotic treatment. Its role in primary prevention is poorly defined and more research is required before changes in practice are recommended.  OBJECTIVE: To systematically review evidence bearing on the management of patients with amyotrophic lateral sclerosis (ALS). METHODS: The authors analyzed studies from 0000 to 0000 to update the 0000 practice parameter. Topics covered in this section include slowing disease progression, nutrition, and respiratory management for patients with ALS. RESULTS: The authors identified 0 Class I studies, 0 Class II studies, and 00 Class III studies in ALS. Important treatments are available for patients with ALS that are underutilized. Noninvasive ventilation (NIV), percutaneous endoscopic gastrostomy (PEG), and riluzole are particularly important and have the best evidence. More studies are needed to examine the best tests of respiratory function in ALS, as well as the optimal time for starting PEG, the impact of PEG on quality of life and survival, and the effect of vitamins and supplements on ALS. Recommendations: Riluzole should be offered to slow disease progression (Level A). PEG should be considered to stabilize weight and to prolong survival in patients with ALS (Level B). NIV should be considered to treat respiratory insufficiency in order to lengthen survival (Level B) and to slow the decline of forced vital capacity (Level B). NIV may be considered to improve quality of life (Level C) [corrected].Early initiation of NIV may increase compliance (Level C), and insufflation/exsufflation may be considered to help clear secretions (Level C).  PMID: 00000000  ]]>By: Steven Novellahttp://theness.com/neurologicablog/index.php/homeopaths-on-the-run/comment-page-0/#comment-00000 Steven NovellaFri, 00 Mar 0000 00:00:00 +0000http://www.theness.com/neurologicablog/?p=0000#comment-00000Wow - reference a foreign language article and then criticize people for interpreting the abstract, which is all they can access in English. Your criticisms are not even substantive - is the abstract wrong, or is this an uncontrolled study? This study is clearly a pragmatic study - the purpose of which is to look at the application of proven therapies in practice - it is not to provide evidence of efficacy. So you linked to a non-efficacy study as if it were evidence of efficacy. And you wonder why we are not impressed. Your other comments were just incoherent. Is it really your claim that I need you to tell me what effective treatments there are for the conditions I treat? Such hubris. But if you want to play - let's focus on ALS. Tell me what magical new treatments you have for ALS that I have somehow missed.Wow - reference a foreign language article and then criticize people for interpreting the abstract, which is all they can access in English.  Your criticisms are not even substantive - is the abstract wrong, or is this an uncontrolled study?  This study is clearly a pragmatic study - the purpose of which is to look at the application of proven therapies in practice - it is not to provide evidence of efficacy. So you linked to a non-efficacy study as if it were evidence of efficacy. And you wonder why we are not impressed.  Your other comments were just incoherent. Is it really your claim that I need you to tell me what effective treatments there are for the conditions I treat? Such hubris.  But if you want to play - let's focus on ALS. Tell me what magical new treatments you have for ALS that I have somehow missed.