Targeted therapy of chronic myeloid leukemia

Inhibition of BCR-ABL with kinase inhibitors has become a well-accepted strategy for targeted therapy of Philadelphia-positive (Ph⁺) chronic myeloid leukemia (CML) and has been shown to be highly effective in controlling the disease. However, BCR-ABL kinase inhibitors do not efficiently kill leukemic stem cells (LSCs), indicating that this therapeutic strategy does not lead to a cure of CML. Development of curative therapies of CML require the identification of genes/pathways that play critical roles in survival and self-renewal of LSCs. Targeting of these key BCR-ABL downstream genes provides an opportunity to eradicate LSCs, as shown in our work that identifies the Alox5 gene as a key regulator of the function of CML LSCs. Immediate clinical trials are necessary to test the effectiveness of targeting a key BCR-ABL downstream gene in eradicating LSCs in CML patients. In this review, we will discuss current targeted therapies of CML using BCR-ABL kinase inhibitors, with a focus on the importance of developing a targeted therapy of CML through identification of target genes in CML LSCs.     

N-linked glycosylation of proteins in the protozoan parasite Toxoplasma gondii

Toxoplasma gondii is an obligate intracellular parasite of animal cells. Infection of humans is common and may result in devastating disease, especially in immunocompromised individuals. Despite previous reports that N-glycosylation of proteins may be a rare post-translational modification in this and related organisms, we demonstrate that it is actually quite prevalent in Toxoplasma. N-Glycosylation is completely inhibited by treatment of parasites with tunicamycin, but this does not appear to exert its major effect on the parasites until they have egressed from their host cells. Although the tunicamycin-treated parasites appear structurally normal at this time they are not motile and mostly incapable of invading new host cells. The few tunicamycin-treated parasites that do invade are severely affected in their ability to replicate and accumulate with a distended endoplasmic reticulum, deformed nuclei, and without recognizable late secretory organelles. We provide experimental evidence that indicate that Toxoplasma N-glycans differ structurally from those in other eukaryotes.     

The effects of 90-day supplementation with the omega-3 essential fatty acid docosahexaenoic acid (DHA) on cognitive function and visual acuity in a healthy aging population

The omega-3 fatty acid docosahexaenoic acid (DHA) is essential for nervous system and retinal development and there is evidence to suggest that DHA deficiencies increase with normal aging. A triple-blind placebo-controlled randomized repeated-measures trial was conducted with 74 healthy participants, aged 45-77 years. Cognitive and visual acuity measures and plasma levels of DHA were determined at baseline and after 90 days of administration of either HiDHA(?) (Clover Corp., Sydney, NSW, Australia: 1000 mg of tuna oil; comprising 252 mg DHA, 60 mg EPA and 10 mg vitamin E) or placebo (1000 mg soybean oil). Ninety days of DHA supplementation was found to significantly raise both plasma DHA and total ω-3 plasma levels in the treatment group, as well as significantly lower total ω-6 levels. However, no significant effects of DHA supplementation on cognitive functioning were found. For participants with corrected vision, the group receiving DHA were found to have significantly better right eye visual acuity posttreatment in comparison with the placebo group (F(1,22) = 7.651; p = 0.011; partial η(2) = 0.258).     

Dairy constituents and neurocognitive health in ageing

Age-related cognitive decline (ARCD) and dementia are of increasing concern to an ageing population. In recent years, there has been considerable research focused on effective dietary interventions that may prevent or ameliorate ARCD and dementia. While a number of studies have considered the impact that dairy products may have on physiological health, particularly with regard to the metabolic syndrome and cardiovascular health, further research is currently needed in order to establish the impact that dairy products have in the promotion of healthy brain function during ageing. The present review considers the available evidence for the positive effects of dairy products on the metabolic syndrome and glucose regulation, with consideration of the implications for neurocognitive health. A literature search of current (September 2010) meta-analyses/reviews and original research regarding dairy products and cognition was conducted through SCOPUS using the following search terms for dairy consituents: dairy, milk, cheese, yoghurt, probiotics, whey protein, alpha lactalbumin, calcium, B-12, bioactive peptides and colostrinin (CLN). These search terms for dairy products were combined with the following search terms related to cognition and health: cognition, cognitive decline, dementia, Alzheimer's disease, metabolic syndrome, diabetes, insulin resistance and glucose regulation. Concerns regarding SFA and other fatty acids found in dairy products are also reviewed in relation to different forms of dairy products. The review also considers recent evidence for positive neurocognitive effects associated with bioactive peptides, CLN and proline-rich polypeptides, α-lactalbumin, vitamin B12, calcium and probiotics. Future directions for the extraction and purification of beneficial constituents are also discussed. It is concluded that low-fat dairy products, when consumed regularly as part of a balanced diet, may have a number of beneficial outcomes for neurocognitive health during ageing.     

Oral pharmacotherapy for overactive bladder in older patients: mirabegron as a potential alternative to antimuscarinics

Objective Overactive bladder (OAB) is a particular challenge to treat in older adults with co-morbid conditions taking multiple medications. Antimuscarinics (e.g., solifenacin, fesoterodine) and β₃-adrenergic receptor agonists (mirabegron) are similarly efficacious; however, antimuscarinics may be associated with side effects that result in poor persistence and contribute to anticholinergic burden, particularly in those taking other medications with anticholinergic properties. With a mechanism of action distinct from antimuscarinics, mirabegron has a different tolerability profile and does not contribute to anticholinergic burden. The objective of this review was to compare and contrast the tolerability profiles of antimuscarinics and mirabegron in older patients to inform practice.

Methods Prospective trials or retrospective subgroup analyses of antimuscarinics for the treatment of OAB in older patients were identified through a search of PubMed. Tolerability data and results of subgroup analyses of mirabegron in patients aged ≥65 and ≥75 years from a pooled analysis of three trials each of 12 weeks and a 1 year trial are described.

Results Anticholinergic adverse events (AEs) including dry mouth and constipation were more frequent with antimuscarinics versus mirabegron. In patients aged ≥65 years, dry mouth occurred with a six-fold higher incidence with tolterodine extended-release (ER) 4?mg than with mirabegron 25?mg or 50?mg over 12 weeks, and a three-fold higher incidence with tolterodine ER than mirabegron 50?mg over 1 year. Mirabegron had a low incidence of central nervous system effects. A systematic review of the cardiovascular safety profile of mirabegron has not identified any clinically significant effects on blood pressure or pulse rate at therapeutic doses amongst patients aged ≥65 years.

Conclusions Mirabegron has a more favorable tolerability profile than antimuscarinics amongst older patients and may provide an improved benefit-to-risk ratio and therefore be considered as an alternative to antimuscarinics for older patients.     

The safety and efficacy of electroconvulsive therapy in patients over age 75

Objectives. To examine the safety and efficacy of electroconvulsive therapy (ECT) in patients over the age of 75 years. Method. Retrospective study of all patients over 75 years treated with ECT in three hospitals between 1995 and 1997. Results. Ninety-three ECT courses were administered during the study period. Ten patients (10.8%) suffered complications following ECT. The most common adverse events were prolonged confusion and hypomania, all of which resolved within 2 weeks of the cessation of treatment. Eighty-five per cent of patients made a marked or moderate response to treatment. Conclusions. ECT is a relatively safe and effective procedure in patients over age 75. Copyright © 1998 John Wiley & Sons, Ltd.