The crisis of no new antibiotics—what is the way forward?

Antibiotic use not only underpins modern medicine, but has brought huge changes to the world, especially in expectations of survival of children into adulthood. The theme of World Health Day, 2011, was "antimicrobial resistance: no action today and no cure tomorrow". The demise of antibacterial drug discovery brings the spectre of untreatable infections. To prevent this crisis immediate action is needed and a new initiative, Antibiotic Action, has been launched. By bringing together communities who need these drugs with academia, health-care professionals, and pharmaceutical companies, this initiative aims to strengthen and enhance academic-industrial partnerships, bring about revision of costly and laborious processes of licensing and regulation of new antibiotics, and address the economics of antimicrobial drugs (cost of use vs profit). A global alliance for antibiotic drug discovery and development would provide a platform for these initiatives.     

Long-term management--the way forward?

The mainstay of treatment for unstable coronary artery disease (UCAD) currently consists of antithrombotic therapy with aspirin plus unfractionated heparin (UFH), together with anti-ischemic treatment with beta blockers and nitrates. Recently, there has been a trend toward replacement of UFH with low-molecular-weight heparins (LMWHs), since these products offer significant advantages over the parent compound. Several lines of evidence suggest that prolongation of treatment with LMWHs beyond the acute phase may be appropriate in patients with UCAD. The Fragmin and Fast Revascularization during InStability in Coronary artery disease (FRISC II) study was designed to evaluate this hypothesis using the LMWH dalteparin sodium (Fragmin). A factorial design was used to randomize patients enrolled in the FRISC II study to an invasive or noninvasive management strategy, and to treatment with dalteparin sodium or placebo. Treatment with dalteparin sodium significantly reduced incidences of death and/or myocardial infarction (MI) during the first months of treatment (the reduction in the relative risk of double endpoint events was statistically significant at 47.0% at 1 month, and remained so at 2 months, but was no longer statistically significant at the 3-month assessment). However, risk, as defined by the triple endpoint of death, MI, and revascularization, was significantly lower (13.0% relative risk reduction) at 3-month follow-up in the treatment group randomized to dalteparin sodium than among patients receiving placebo. In patients in whom revascularization procedures were carried out, the risk of new, postprocedural events was low in both the placebo and dalteparin sodium arms. Thus, dalteparin sodium appears to protect patients from cardiac events until they undergo invasive procedures, and it can therefore be used as a bridge to revascularization.     

Screening for lung cancer: Is this the way forward?

While low-dose CT scans have been shown to detect greater numbers of early lung cancers than conventional CXR, the first randomized trial of CT versus CXR screening in more than 50 000 subjects has shown a 20% reduction in mortality with CT. There are several other randomized trials in progress. CT scanning may be a useful technique for identifying lung cancer at an earlier stage and may reduce mortality. However, before it can be used on a wider scale, issues such as overdiagnosis bias, cost-effectiveness, false positive findings of multiple noncalcified nodules and the willingness of the relevant population to accept CT scanning need to be evaluated. There is still very little information on the cost per life-year saved as a result of CT scanning, as the data to date is very imprecise. There is no evidence that screening programs influence smoking rates despite the inclusion of cessation programs in many trials. Furthermore, if CT screening is adopted, much work is needed to persuade individuals at high risk, mostly current or former heavy smokers with some airflow obstruction, to participate in a screening program.     

Evolving concepts in classification of systemic vasculitis: where are we and what is the way forward?

The classification of the systemic vasculitides has been controversial for several decades. The Chapel Hill consensus Conference definitions originally developed in 1994, but revised and extended in 2012 are now widely accepted. The American College of Rheumatology (ACR) criteria were first published in 1990, are now generally accepted to be out of date and new criteria are needed. More recently the classical division of the ANCA vasculitides using clinical phenotype has come under scrutiny with evidence from epidemiological, genetic and outcome studies that perhaps these conditions should be classified on the basis of ANCA specificity into PR3‐ANCA positive and MPO‐ANCA positive groups. The traditional distinction between giant cell arteritis and Takayasu arteritis has been questioned and some recent studies of GCA have included patients with only extra‐cranial disease. The Diagnostic and Classification Criteria of Vasculitis study (DCVAS) will provide new validated classification criteria for the systemic vasculitides.     

ATP-binding cassette transporters in progression and clinical outcome of pancreatic cancer: What is the way forward?

Pancreatic ductal adenocarcinoma(PDAC) is one of the most aggressive diseases and is characterized by high chemoresistance, leading to the lack of effective therapeutic approaches and grim prognosis. Despite increasing understanding of the mechanisms of chemoresistance in cancer and the role of ATPbinding cassette(ABC) transporters in this resistance, the therapeutic potential of their pharmacological inhibition has not been successfully exploited yet. In spite of the discovery of potent pharmacological modulators of ABC transporters, the results obtained in clinical trials have been so far disappointing, with high toxicity levels impairing their successful administration to the patients. Critically, although ABC transporters have been mostly studied for their involvement in development of multidrug resistance(MDR), in recent years the contribution of ABC transporters to cancer initiation and progression has emerged as an important area of research, the understanding of which could significantly influence the development of more specific and efficient therapies. In this review, we explore the role of ABC transporters in the development and progression of malignancies, with focus on PDAC. Their established involvement in development of MDR will be also presented. Moreover, an emerging role for ABC transporters as prognostic tools for patients' survival will be discussed, demonstrating the therapeutic potential of ABC transporters in cancer therapy.