Pulmonary arterial hypertension: Navigating the pathways of progress in diagnosis, treatment, and patient care.

Pulmonary arterial hypertension (PAH) is a form of precapillary pulmonary hypertension caused by a complex process of endothelial dysfunction and vascular remodeling. If left untreated, this progressive disease presents with symptoms of incapacitating fatigue causing marked loss of quality of life, eventually culminating in right ventricular failure and death. Patient management is complex and based on accurate diagnosis, risk stratification, and treatment initiation, with close monitoring of response and disease progression. Understanding the underlying pathophysiology has enabled the development of multiple drugs directed at different targets in the pathological chain. Vasodilator therapy has been the mainstay approach for the last few years, significantly improving quality of life, functional status, and survival. Recent advances in therapies targeting dysfunctional pathways beyond endothelial dysfunction may address the fundamental processes underlying the disease, raising the prospect of increasingly effective options for this high-risk group of patients with a historically poor prognosis.

Chronic thromboembolic pulmonary hypertension: A comprehensive review of pathogenesis, diagnosis, and treatment strategies.

Chronic thromboembolic pulmonary hypertension (CTEPH) is part of group 4 of the pulmonary hypertension (PH) classification and generally affects more than a third of patients referred to PH centers. It is a three-compartment disease involving proximal (lobar-to-segmental) and distal (subsegmental) pulmonary arteries that are obstructed by persistent fibrothrombotic material, and precapillary pulmonary arteries that can be affected as in pulmonary arterial hypertension. It is a rare complication of pulmonary embolism (PE), with an incidence of around 3% in PE survivors. The observed incidence of CTEPH in the general population is around six cases per million but could be three times higher than this, as estimated from PE incidence. However, a previous venous thromboembolic episode is not always documented. With advances in multimodality imaging and therapeutic management, survival for CTEPH has improved for both operable and inoperable patients. Advanced imaging with pulmonary angiography helps distinguish proximal from distal obstructive disease. However, right heart catheterization is of utmost importance to establish the diagnosis and hemodynamic severity of PH. The therapeutic strategy relies on a stepwise approach, starting with an operability assessment. Pulmonary endarterectomy (PEA), also known as pulmonary thromboendarterectomy, is the first-line treatment for operable patients. Growing experience and advances in surgical technique have enabled expansion of the distal limits of PEA and significant improvements in perioperative and mid- to long-term mortality. In patients who are inoperable or who have persistent/recurrent PH after PEA, medical therapy and/or balloon pulmonary angioplasty (BPA) are effective treatment options with favorable outcomes that are increasingly used. All treatment decisions should be made with a multidisciplinary team that includes a PEA surgeon, a BPA expert, and a chest radiologist.

Sustained NMDA receptor hypofunction impairs brain-derived neurotropic factor signalling in the PFC, but not in the hippocampus, and disturbs PFC-dependent cognition in mice.

BACKGROUND: Cognitive deficits profoundly impact on the quality of life of patients with schizophrenia. Alterations in brain derived neurotrophic factor (BDNF) signalling, which regulates synaptic function through the activation of full-length tropomyosin-related kinase B receptors (TrkB-FL), are implicated in the aetiology of schizophrenia, as is N-methyl-D-aspartate receptor (NMDA-R) hypofunction. However, whether NMDA-R hypofunction contributes to the disrupted BDNF signalling seen in patients remains unknown. AIMS: The purpose of this study was to characterise BDNF signalling and function in a preclinical rodent model relevant to schizophrenia induced by prolonged NMDA-R hypofunction. METHODS: Using the subchronic phencyclidine (PCP) model, we performed electrophysiology approaches, molecular characterisation and behavioural analysis. RESULTS: The data showed that prolonged NMDA-R antagonism, induced by subchronic PCP treatment, impairs long-term potentiation (LTP) and the facilitatory effect of BDNF upon LTP in the medial prefrontal cortex (PFC) of adult mice. Additionally, TrkB-FL receptor expression is decreased in the PFC of these animals. By contrast, these changes were not present in the hippocampus of PCP-treated mice. Moreover, BDNF levels were not altered in the hippocampus or PFC of PCP-treated mice. Interestingly, these observations are paralleled by impaired performance in PFC-dependent cognitive tests in mice treated with PCP. CONCLUSIONS: Overall, these data suggest that NMDA-R hypofunction induces dysfunctional BDNF signalling in the PFC, but not in the hippocampus, which may contribute to the PFC-dependent cognitive deficits seen in the subchronic PCP model. Additionally, these data suggest that targeting BDNF signalling may be a mechanism to improve PFC-dependent cognitive dysfunction in schizophrenia.

Challenges of BDNF-based therapies: From common to rare diseases.

Neurotrophins are a well-known family of neurotrophic factors that play an important role both in the central and peripheral nervous systems, where they modulate neuronal survival, development, function and plasticity. Brain-derived neurotrophic factor (BDNF) possesses diverse biological functions which are mediated by the activation of two main classes of receptors, the tropomyosin-related kinase (Trk) B and the p75 neurotrophin receptor (p75NTR). The therapeutic potential of BDNF has drawn attention since dysregulation of its signalling cascades has been suggested to underlie the pathogenesis of both common and rare diseases. Multiple strategies targeting this neurotrophin have been tested; most have found obstacles that ultimately hampered their effectiveness. This review focuses on the involvement of BDNF and its receptors in the pathophysiology of Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Rett Syndrome (RTT). We describe the known mechanisms leading to the impairment of BDNF/TrkB signalling in these disorders. Such mechanistic insight highlights how BDNF signalling compromise can take various shapes, nearly disease-specific. Therefore, BDNF-based therapeutic strategies must be specifically tailored and are more likely to succeed if a combination of resources is employed.