Supportive and symptomatic management of amyotrophic lateral sclerosis

The main aims in the care of individuals with amyotrophic lateral sclerosis (ALS) are to minimize morbidity and maximize quality of life. Although no cure exists for ALS, supportive and symptomatic care provided by a specialist multidisciplinary team can improve survival. The basis for supportive management is shifting from expert consensus guidelines towards an evidence-based approach, which encourages the use of effective treatments and could reduce the risk of harm caused by ineffective or unsafe interventions. For example, respiratory support using noninvasive ventilation has been demonstrated to improve survival and quality of life, whereas evidence supporting other respiratory interventions is insufficient. Increasing evidence implicates a causal role for metabolic dysfunction in ALS, suggesting that optimizing nutrition could improve quality of life and survival. The high incidence of cognitive dysfunction and its impact on prognosis is increasingly recognized, although evidence for effective treatments is lacking. A variety of strategies are used to manage the other physical and psychological symptoms, the majority of which have yet to be thoroughly evaluated. The need for specialist palliative care throughout the disease is increasingly recognized. This Review describes the current approaches to symptomatic and supportive care in ALS and outlines the current guidance and evidence for these strategies

OrthoList: A Compendium of C. elegans Genes with Human Orthologs

C. elegans is an important model for genetic studies relevant to human biology and disease. We sought to assess the orthology between C. elegans and human genes to understand better the relationship between their genomes and to generate a compelling list of candidates to streamline RNAi-based screens in this model.We performed a meta-analysis of results from four orthology prediction programs and generated a compendium, "OrthoList", containing 7,663 C. elegans protein-coding genes. Various assessments indicate that OrthoList has extensive coverage with low false-positive and false-negative rates. Part of this evaluation examined the conservation of components of the receptor tyrosine kinase, Notch, Wnt, TGF-ß and insulin signaling pathways, and led us to update compendia of conserved C. elegans kinases, nuclear hormone receptors, F-box proteins, and transcription factors. Comparison with two published genome-wide RNAi screens indicated that virtually all of the conserved hits would have been obtained had just the OrthoList set (∼38% of the genome) been targeted. We compiled Ortholist by InterPro domains and Gene Ontology annotation, making it easy to identify C. elegans orthologs of human disease genes for potential functional analysis.We anticipate that OrthoList will be of considerable utility to C. elegans researchers for streamlining RNAi screens, by focusing on genes with apparent human orthologs, thus reducing screening effort by ∼60%. Moreover, we find that OrthoList provides a useful basis for annotating orthology and reveals more C. elegans orthologs of human genes in various functional groups, such as transcription factors, than previously described

Combination of novel and public RNA-seq datasets to generate an mRNA expression atlas for the domestic chicken

Background: The domestic chicken (Gallus gallus) is widely used as a model in developmental biology and is also an important livestock species. We describe a novel approach to data integration to generate an mRNA expression atlas for the chicken spanning major tissue types and developmental stages, using a diverse range of publicly-archived RNA-seq datasets and new data derived from immune cells and tissues. Results: Randomly down-sampling RNA-seq datasets to a common depth and quantifying expression against a reference transcriptome using the mRNA quantitation tool Kallisto ensured that disparate datasets explored comparable transcriptomic space. The network analysis tool Graphia was used to extract clusters of co-expressed genes from the resulting expression atlas, many of which were tissue or cell-type restricted, contained transcription factors that have previously been implicated in their regulation, or were otherwise associated with biological processes, such as the cell cycle. The atlas provides a resource for the functional annotation of genes that currently have only a locus ID. We cross-referenced the RNA-seq atlas to a publicly available embryonic Cap Analysis of Gene Expression (CAGE) dataset to infer the developmental time course of organ systems, and to identify a signature of the expansion of tissue macrophage populations during development. Conclusion: Expression profiles obtained from public RNA-seq datasets - despite being generated by different laboratories using different methodologies - can be made comparable to each other. This meta-analytic approach to RNA-seq can be extended with new datasets from novel tissues, and is applicable to any species

Sixteen-year single-surgeon experience with coil embolization for ruptured intracranial aneurysms: recurrence rates and incidence of late rebleeding. Clinical article.

OBJECT: Over a 16-year period, 570 patients presenting with acute aneurysmal subarachnoid hemorrhage were successfully treated using endosaccular coil embolization within 30 days of hemorrhage by a single surgeon. Patients were followed to assess the stability of aneurysm occlusion and its longer-term efficacy in protecting against rebleeding. METHODS: Patients were followed for 6 to 191 months (mean 73.7 months, median 67 months) by clinical review, angiography performed at 6 and 24 months posttreatment, and questionnaires sent via the postal service every 5 years. Late rebleeding was defined as > 30 days after treatment. RESULTS: Stable angiographic occlusion was evident in 74.5% of small, 72.2% of large, and 60% of giant aneurysms. Recurrent filling was found in 119 (26.3%) of 452 aneurysms. Rebleeding was diagnosed in 9 patients (6 treated aneurysms) and occurred between 2 and 114 months posttreatment. It was due to aneurysm recurrence in 6 patients, rupture of a coincidental untreated aneurysm in 2 patients, and rupture of a de novo aneurysm in 1 patient. Rebleeding occurred in 3 (2.5%) of 119 unstable aneurysms and in 3 (0.9%) of 333 stable aneurysms, as seen on initial follow-up angiography studies. Annual rebleeding rates ranged from 0.2% to 0.6% for all causes and from 0.2% to 0.4% for rebleeding of treated aneurysms. No rebleeding was recorded after the first decade, with 138 patients having more than 10 years of follow-up. CONCLUSIONS: Periodic follow-up with angiographic studies after coil embolization is recommended to identify aneurysm recurrence and patients at a high risk of late rebleeding in the medium term. More frequent follow-up is recommended for patients harboring coincidental unruptured aneurysms