The anti-Parkinsonian effect of glutamate metabotropic group 5 (mGluR5) and adenosine A 2A receptor antagonists is believed to result from their ability to postsynaptically control the responsiveness of the indirect pathway that is hyperfunctioning in Parkinson's disease. mGluR5 and A 2A antagonists are also neuroprotective in brain injury models involving glutamate excitotoxicity. Thus, we hypothesized that the antiParkinsonian and neuroprotective effects of A 2A and mGluR5 receptors might be related to their control of striatal glutamate release that actually triggers the indirect pathway. The A 2A agonist, CGS21680 (1-30 nM) facilitated glutamate release from striatal nerve terminals up to 57%, an effect prevented by the A 2A antagonist, SCH58261 (50 nM). The mGluR5 agonist, CHPG (300-600 lM) also facilitated glutamate release up to 29%, an effect prevented by the mGluR5 antagonist, MPEP (10 lM). Both mGluR5 and A 2A receptors were located in the active zone and 57 ± 6% of striatal glutamatergic nerve terminals possessed both A 2A and mGluR5 receptors, suggesting a presynaptic functional interaction. Indeed, submaximal concentrations of CGS21680 (1 nM) and CHPG (100 lM) synergistically facilitated glutamate release and the facilitation of glutamate release by 10 nM CGS21680 was prevented by 10 lM MPEP, whereas facilitation by 300 lM CHPG was prevented by 10 nM SCH58261. These results provide the first direct evidence that A 2A and mGluR5 receptors are co-located in more than half of the striatal glutamatergic terminals where they facilitate glutamate release in a synergistic manner. This emphasizes the role of the modulation of glutamate release as a likely mechanism of action of these receptors both in striatal neuroprotection and in Parkinson's disease.
Neurodegeneration is a process transversal to neuropsychiatric diseases and the understanding of its mechanisms should allow devising strategies to prevent this irreversible step in brain diseases. Neurodegeneration caused by seizures is a critical step in the aggravation of temporal lobe epilepsy, but its mechanisms remain undetermined. Convulsions trigger an elevation of extracellular adenosine and upregulate adenosine A2A receptors (A2AR), which have been associated with the control of neurodegenerative diseases. Using the rat and mouse kainate model of temporal lobe epilepsy, we now tested whether A2AR control convulsions-induced hippocampal neurodegeneration. The pharmacological or genetic blockade of A2AR did not affect kainate-induced convulsions but dampened the subsequent neurotoxicity. This neurotoxicity began with a rapid A2AR upregulation within glutamatergic synapses (within 2 h), through local translation of synaptic A2AR mRNA. This bolstered A2AR-mediated facilitation of glutamate release and of long-term potentiation (LTP) in CA1 synapses (4 h), triggered a subsequent synaptotoxicity, heralded by decreased synaptic plasticity and loss of synaptic markers coupled to calpain activation (12 h), that predated overt neuronal loss (24 h). All modifications were prevented by the deletion of A2AR selectively in forebrain neurons. This shows that synaptic A2AR critically control synaptic excitotoxicity, which underlies the development of convulsions-induced neurodegeneration.
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with a dismal survival rate of only 3 years and no curative pharmacological therapy. The recent approval of 2 anti-fibrotic drugs (nintedanib and pirfenidone) that slow disease progression has provided some hope for patients. However, effectively managing anti-fibrotic treatment can be a challenge due to tolerability issues, the presence of pulmonary and extra-pulmonary comorbidities, and the need for concomitant medications in many patients. In general, making clear evidence-based decisions can be difficult for physicians because patients with comorbidities are often excluded from clinical trials. Since currently anti-fibrotic drugs are the only effective therapeutics capable of slowing disease progression, it is imperative that all treatment options are thoroughly evaluated and exhausted in each individual, irrespective of complicating factors, to permit the best outcome for the patient. In this review, we present data from clinical trials, post hoc analyses, post-marketing surveillance, and real-world studies that are relevant to the management of nintedanib treatment. In addition, we also provide practical recommendations developed by a multidisciplinary panel of experts for the management of nintedanib treatment in patients with IPF associated complications and those experiencing gastrointestinal side effects.
Occupational lung diseases (OLDs) are related to the exposure and inhalation of organic, inorganic, and synthetic particles, fumes, gases, or infectious agents. From the long list of OLDs this article focuses the discussion on bronchoalveolar lavage (BAL) in parenchymal immunoinflammatory conditions, such as hypersensitivity pneumonitis (HP) and pneumoconiosis.Several antigens may cause HP, including products of plant or animal origin, aerosolized microorganisms, and organic chemicals. BAL is used not only to assess the pathogenesis of these diseases but also to identify the typical pattern of intense lymphocytic alveolitis, usually with a CD4:CD8 ratio below normal and frequently with the presence of mast cells, plasma cells, and foamy macrophages.Pneumoconioses are chronic interstitial lung diseases caused by the inhalation of mineral and metallic inorganic particles/dusts in an occupational setting, showing a decreasing prevalence in recent years.BAL is a useful tool not only to express the complex pathogenic mechanisms of these entities but also in excluding other diagnoses and causes of alveolitis, and to document specific exposures, such as the identification of asbestos bodies (ABs) in asbestosis or the proliferative response of BAL lymphocytes to beryllium in chronic beryllium disease (CBD).
The PERSEIDS study aimed to estimate incidence/prevalence of interstitial lung diseases (ILDs), fibrosing Interstitial lung diseases (F-ILDs), idiopathic pulmonary fibrosis (IPF), systemic sclerosis-associated ILD (SSc-ILD), other non-IPF F-ILDs and their progressive-fibrosing (PF) forms in six European countries, as current data are scarce.This retrospective, two-phase study used aggregate data (2014–2018). In Phase 1, incident/prevalent cases of ILDs above were identified from clinical databases through an algorithm based on codes/keywords, and incidence/prevalence was estimated. For non-IPF F–ILDs, the relative percentage of subtypes was also determined. In Phase 2, a subset of non-IPF F-ILD cases was manually reviewed to determine the percentage of PF behaviour and usual interstitial pneumonia-like (UIP-like) pattern. A weighted mean percentage of progression was calculated for each country and used to extrapolate incidence/prevalence of progressive-fibrosing ILDs (PF–ILDs).In 2018, incidence/105 person-years ranged between 9.4–83.6(ILDs), 7.7–76.2(F-ILDs), 0.4–10.3(IPF), 6.6–71.7(non-IPF F-ILDs) and 0.3–1.5(SSc-ILD); and prevalence/105 persons ranged between 33.6–247.4(ILDs), 26.7–236.8(F-ILDs), 2.8–31.0(IPF), 22.3–205.8(non-IPF F-ILDs) and 1.4–10.1(SSc-ILD). Among non-IPF F-ILDs, sarcoidosis was the most frequent subtype. PF behaviour and UIP-like pattern were present in a third of non-IPF F-ILD cases each and hypersensitivity pneumonitis showed the highest percentage of progressive behaviour. Incidence of PF-ILDs ranged between 2.1–14.5/105 person-years, and prevalence between 6.9–78.0/105 persons.To our knowledge, PERSEIDS is the first study assessing incidence, prevalence and rate of progression of ILDs across several European countries. Still below the threshold for orphan diseases, the estimates obtained were higher and more variable than reported in previous studies, but differences in study design/population must be considered.
Coffee consumption was associated with some positive effects on the respiratory system. There was however limited available evidence, mostly from cross sectional and retrospective studies. The only prospective cohort studies were those reporting on respiratory mortality. These results suggest that coffee consumption may be a part of a healthy lifestyle leading to reduced respiratory morbidity.
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People with rare lung diseases often suffer the burden of delayed diagnosis, limited treatment options, and difficulties in finding expert physicians. One of the reasons for the delay in diagnosis is the limited training for healthcare practitioners on rare diseases. This review explores the main concerns and needs for education on rare lung diseases from the perspectives of both patients and professionals. Despite the increasing interest in rare lung disorders and some recent breakthrough developments on the management of several diseases, healthcare professionals, including general practitioners and hospital workers, receive little education on this topic. Nonetheless, many healthcare professionals show much interest in receiving further training, especially on diagnosis. Patients and families want easier access to high-quality education materials to help them manage their own disease. Well-educated patients are better equipped to deal with chronic diseases, but patient education can be challenging as patients’ individual health issues, and diverse backgrounds can create significant barriers. Raising more awareness for rare lung diseases and further development of patient-centred international expert networks like the European Reference Network on Rare Lung Diseases (ERN-LUNG), which includes both experts and patient representatives, are essential for improving care and education on rare lung diseases. Initiatives such as the Rare Disease Day, have been successful in increasing awareness for rare conditions. The development of online tools for accessing information has had positive effects and should be further supported and extended in the future.
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