Explore the vast range of titles available.

Gene therapies for genetic diseases have been sought for decades, and the relatively recent development of the CRISPR/Cas9 gene-editing system has encouraged a new wave of interest in the field. There have nonetheless been significant setbacks to gene therapy, including unintended biological consequences, ethical scandals, and death. The major focus of research has been on technological problems such as delivery, potential immune responses, and both on and off-target effects in an effort to avoid negative clinical outcomes. While the field has concentrated on how we can better achieve gene therapies and gene editing techniques, there has been less focus on when and why we should use such technology. Here we combine discussion of both the technical and ethical barriers to the widespread clinical application of gene therapy and gene editing, providing a resource for gene therapy experts and novices alike. We discuss ethical problems and solutions, using cystic fibrosis and beta-thalassemia as case studies where gene therapy might be suitable, and provide examples of situations where human germline gene editing may be ethically permissible. Using such examples, we propose criteria to guide researchers and clinicians in deciding whether or not to pursue gene therapy as a treatment. Finally, we summarize how current progress in the field adheres to principles of biomedical ethics and highlight how this approach might fall short of ethical rigour using examples in the bioethics literature. Ultimately by addressing both the technical and ethical aspects of gene therapy and editing, new frameworks can be developed for the fair application of these potentially life-saving treatments.

Great improvements have been made in acute lymphoblastic leukemia (ALL) treatment in the past decades, especially due to the use of L-asparaginase (L-ASP). Despite the significant success rate, several side effects mainly caused by toxicity, asparaginase silent inactivation, and cellular resistance, encourage an open debate regarding the optimal dosage and formulation of L-ASP. Alternative sources of asparaginases have been constantly investigated in order to overcome hypersensitivity clinical toxicity. Additionally, genomic modulation as gene expression profiling, genetic polymorphisms, and epigenetic changes is also being investigated concerning their role in cellular resistance to L-ASP. Understanding the mechanisms that mediate the resistance to L-ASP treatment may bring new insights into ALL pathobiology and contribute to the development of more effective treatment strategies. In summary, this review presents an overview on L-ASP data and focuses on cellular mechanisms underlying resistance and alternative therapies for the use of asparaginase in childhood ALL treatment.

[...]the combination of symptom severity (or at least refractoriness to other interventions), presence of an active anxiety or affective disorder, and features of somatisation disorder weigh into the initial treatment decisions with antidepressants (fig 1).

TOXICITY ASSOCIATED WITH INTRAVENOUS CYCLOSPORIN Of 111 patients with inflammatory bowel disease treated with intravenous cyclosporin 4 mg/kg/day, the most common toxic effects were paresthesias (51%), hypertension (43%), and hypomagnesaemia (42%). Low dose intravenous cyclosporin (2 mg/kg/day) may be associated with lower rates of toxicity. 5 Both hypocholesterolaemia (serum cholesterol less than 120 mg/dl) and hypomagnesaemia (serum magnesium less than 1.5 mg/dl) significantly increase the risk of seizures in patients treated with intravenous cyclosporin. 9 Summary Intravenous cyclosporin (with or without continued intravenous corticosteroids) is effective in 50-80% of patients with severe ulcerative colitis.

The rationale for using probiotics in inflammatory bowel disease (IBD) is based on persuasive evidence implicating intestinal bacteria in the pathogenesis of IBD. 1 2 The most compelling evidence is derived from animal models; despite great diversity in genetic defects and immunopathology, a consistent feature is dependency on the presence of normal enteric flora for full expression of disease. [...]probiotics may offer a simple adjunct to conventional therapy and empower patients with a sense of control by shifting the emphasis of diet from one of nutritional replenishment alone to a more functional role.

Theoretically, with such targeted delivery, the combination of increased topical potency and low systemic availability should provide benefits (improved efficacy with less systemic side effects) compared with conventional glucocorticoids. 4 However, due to the increased potency at the steroid receptor (100 times that of hydrocortisone), suppression of the hypothalamic-pituitary-adrenal axis can occur with treatment. 12 Budesonide in a controlled ileal release formulation, administered as 9 mg/day, has been shown to be efficacious for active ileal and ileocecal Crohn's disease. 12- 15 In addition to the reduction in intestinal symptoms and signs assessed by the Crohn's disease activity index, budesonide successfully improved quality of life as assessed by the inflammatory bowel disease questionnaire16 and extraintestinal arthritic manifestations associated with active Crohn's disease.17 The controlled ileal release formulation of budesonide has also been used to \"switch\" patients from prednisone with a 4-10 week transition and follow up for an additional three months of sustained clinical benefits and reduced steroid associated toxicity18 but, like other corticosteroids, at doses of 3-6 mg/day budesonide was ineffective for the maintenance of remission at one year19-21 or for the prevention of postoperative recurrence.22, 23 Overall, compared with conventional steroids, the better side effect profile of budesonide is balanced by somewhat lower efficacy than conventional steroids in treating active disease. 13, 14, 24 Key points Non-systemic steroids for IBD have increased potency and first pass metabolism Rectal (enema) formulations are effective for active distal ulcerative colitis, but not as efficacious as rectal mesalamine Controlled (delayed) release budesonide is effective for active ileal and right colonic Crohn's disease with a low side effect profile Similar to other corticosteroids, no maintenance benefits have been identified for non-systemic steroids used on a long term (one year) basis In summary, the concept of separating the mucosal effects of glucocorticoids from the systemic effects has been demonstrated in both ulcerative colitis and Crohn's disease.

[...]the pathophysiology of increased bone fragility in IBD has not been clearly established and may differ from that of postmenopausal osteoporosis. [...]as noted above, osteoporosis associated with IBD may affect younger men and premenopausal women, groups that have not been subjected to trials of therapeutic intervention outside the context of glucocorticoid induced osteoporosis.

There are case reports of severe colitis complicating the use of methotrexate, although not yet in patients with Crohn's disease. 9 There is an increased risk of opportunistic infections, including herpes zoster and pneumocystis carinii pneumonia, but not of neoplasia other than lymphoproliferative disorders. 10 The latter are related to previous infection with Epstein-Barr virus, and are sometimes reversible on methotrexate withdrawal. Because methotrexate is teratogenic, pregnancy or conception within six months of stopping treatment with methotrexate of either partner should be avoided.