Modelo Point-of-Care Ultrasound en Atención Primaria: ¿herramienta de alta resolución?

Point-of-Care Ultrasound is a method of performing a rapid clinical ultrasound, with the aim of responding to a clinical question immediately. This is not an ultrasound performed systematically as the radiologists do, nor does it pretend to replace it. It is useful in some kind of screening (abdominal aortic aneurysm) and is of special interest in ultrasound-guided procedures (joint infiltration by injection).It allows to adapt the derivations, minimising the uncertainty, ruling out certain pathologies due to its high diagnostic precision. It can also lead to overdiagnosis, if the examinations carried out are not limited to the organs on which our clinical suspicion is based.Ultrasound is one tool more in the diagnostic process, but its use must be limited to certain clinical situations. Its use in early detection of prevalent diseases in Primary Care should be properly evaluated. On the other hand with more evidence of a high diagnostic accuracy in a large list of pathological conditions.     

Will biomarker-based diagnosis of Alzheimer’s disease maximize scientific progress? Evaluating proposed diagnostic criteria

A recently published framework for the diagnosis of Alzheimer’s disease (AD) in research studies would allow diagnosis on the sole basis of two biomarkers (β-amyloid and pathologic tau), even in people with no objective or subjective memory or cognitive changes. This revision will have substantial implications for future Alzheimer’s research, and the changes should be rigorously evaluated before widespread adoption. We propose three principles for evaluating any revision to diagnostic frameworks for AD: (1) does the revision improve the validity of the diagnosis; (2) does the revision improve the reliability or reduce the expense of the diagnosis; and (3) will the revision foster innovative and rigorous research across populations. The new diagnostic framework is unlikely to achieve any of these goals. Instead, it has the potential to handicap future researchers, and slow progress towards identifying effective strategies to prevent or treat AD.     

Notch signaling as a therapeutic target for acute lymphoblastic leukemia

Introduction: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Although the therapy of ALL has significantly improved, the heterogeneous genetic landscape of the disease often causes relapse, which is difficult to treat. Achieving a positive outcome for patients with relapsed or refractory ALL remains a challenging issue. The high prevalence of NOTCH-activating mutations in T-cell acute lymphoblastic leukemia (T-ALL) and the central role of NOTCH signaling in regulating cell survival and growth of ALL provide a rationale for the development of Notch signaling-targeted strategies in this disease. Therapeutic alternatives with effective anti-leukemic potential and low toxicity are needed.

Areas covered: This review provides an overview of the currently available drugs directly or indirectly targeting Notch signaling in ALL. Besides considering the known Notch targeting approaches, such as γ-secretase inhibitors (GSIs) and Notch inhibiting antibodies (mAbs), currently in clinical trials, we focus on the recent insights into the molecular mechanisms underlying the Notch signaling regulation in ALL.

Expert opinion: Novel drugs targeting specific steps of Notch signaling or intersecting pathways could improve the efficiency of the conventional hematological cancers therapies. Further studies are required to translate the new findings into future clinical applications.     

GRK2 as a therapeutic target for heart failure

Introduction: G protein-coupled receptor (GPCR) kinase-2 (GRK2) is a regulator of GPCRs, in particular β-adrenergic receptors (ARs), and as demonstrated by decades of investigation, it has a pivotal role in the development and progression of cardiovascular disease, like heart failure (HF). Indeed elevated levels and activity of this kinase are able to promote the dysfunction of both cardiac and adrenal α- and β-ARs and to dysregulate other protective signaling pathway, such as sphingosine 1-phospate and insulin. Moreover, recent discoveries suggest that GRK2 can signal independently from GPCRs, in a ‘non-canonical’ manner, via interaction with non-GPCR molecule or via its mitochondrial localization.

Areas covered: Based on this premise, GRK2 inhibition or its genetic deletion has been tested in several disparate animal models of cardiovascular disease, showing to protect the heart from adverse remodeling and dysfunction.

Expert opinion: HF is one of the leading cause of death worldwide with enormous health care costs. For this reason, the identification of new therapeutic targets like GRK2 and strategies such as its inhibition represents a new hope in the fight against HF development and progression. Herein, we will update the readers about the ‘state-of-art’ of GRK2 inhibition as a potent therapeutic strategy in HF.     

Safety of humanized monoclonal antibodies against IL-5 in asthma: focus on reslizumab

Introduction: Reslizumab, a humanized mAb against IL-5, reduces the number of eosinophils in the blood and lungs. Based on efficacy and safety data from pivotal RCTs, reslizumab had been approved for use as an add-on maintenance treatment of severe asthma with an eosinophilic phenotype in adults who have a history of exacerbations despite receiving their current asthma medicines.

Areas covered: Current literature on reslizumab has been reviewed with a specific focus on its safety profile in the treatment of severe asthma.

Expert opinion: Large pivotal and supportive trials reinforce the view that reslizumab is well tolerated, with an acceptable safety profile in patients exposed for longer than 2 years. However, no or few data concerning safety in special populations such as smokers, those with immune- and cellular senescence, patients with comorbidities and those receiving multi-drug treatments are available as yet. Furthermore, we need to fully elucidate some fundamental issues such as the risk of anaphylaxis and the long-term risk-benefit ratio of the impact of depletion of eosinophils and the potential risk of malignancies induced by a treatment with this anti-IL-5 agent.