Exon skipping for nonsense mutations in Duchenne muscular dystrophy: too many mutations, too few patients?

Introduction: Duchenne muscular dystrophy (DMD), one of the most common and lethal genetic disorders, is caused by mutations of the dystrophin gene. Removal of an exon or of multiple exons using antisense molecules has been demonstrated to allow synthesis of truncated 'Becker muscular dystrophy-like' dystrophin. Areas covered: Approximately 15% of DMD cases are caused by a nonsense mutation. Although patient databases have previously been surveyed for applicability to each deletion mutation pattern, this is not so for nonsense mutations. Here, we examine the world-wide database containing notations for more than 1200 patients with nonsense mutations. Approximately 47% of nonsense mutations can be potentially treated with single exon skipping, rising to 90% with double exon skipping, but to reach this proportion requires the development of exon skipping molecules targeting some 68 of dystrophin's 79 exons, with patient numbers spread thinly across those exons. In this review, we discuss progress and remaining hurdles in exon skipping and an alternative strategy, stop-codon readthrough. Expert opinion: Antisense-mediated exon skipping therapy is targeted highly at the individual patient and is a clear example of personalized medicine. An efficient regulatory path for drug approval will be a key to success.     

Immune and cell therapy in type 1 diabetes: too little too late?

INTRODUCTION: Type 1 diabetes is caused by autoimmune destruction of insulin-producing β-cells. Intensive insulin therapy protects most patients against chronic complications of diabetes, but exposes patients to acute complications like hypoglycaemia and impacts on quality of life. Therapies that aim at protecting or restoring endogenous insulin secretion might help in decreasing the risk of severe hypoglycemia and long-term complications. AREAS COVERED: This article reviews the literature of clinical immunotherapy and β-cell transplantation in treatment of type 1 diabetes with specific focus on the effect on preserving and restoring β-cell mass. EXPERT OPINION: Several studies in recent-onset type 1 diabetic patients have provided proof of principle that immunotherapy can preserve residual functional β-cell mass. The observation that this strategy is most effective early in the disease process opens possibilities of arresting and even preventing type 1 diabetes. In patients with too few or no surviving β-cells, current protocols of β-cell transplantation can restore functional β-cell mass up to 25% of levels in healthy controls. Unfortunately, both strategies to date are followed by progressive decline of endogenous insulin secretion later on. Strategies to restore functional β-cell mass to a higher level and to restore immune tolerance are thus needed.     

Distractors--can they be biased too?

Numerous work has been done on item bias and differential item functioning. Although there is some research on distractor analysis, no detailed study has been attempted to examine the way distractors in an item function, with regards to comparing distractor performance. This paper examines how distractors function differentially and compares various methods for identifying this. The Pearson chi-square, likelihood ratio chi-square and Neyman weighted least squares chi-square tests are some of these methods. Possible causes of distractor bias are discussed with illustrations from a physics problem-solving scale.     

Is enough oxygen too much?

Human cells require O₂ for their energy supply, and critical illness can threaten the efficient delivery of O₂ in accordance with tissue metabolic needs. In the accompanying article, Martin and colleagues point out that hypoxia is a normal and well-tolerated stress during embryonic development. A better understanding of how fetal cells survive these conditions and how adult cells adapt to high altitude exposure may provide insight into how these mechanisms might be engaged in the treatment of hypoxemic patients. They suggest that 'permissive hypoxia' represents a therapeutic possibility. But before we turn down the inspired O₂ levels we should consider the broader effects of hypoxia on tissue repair in critical illness.