Tiago M. Alfaro

Co‐localization and functional interaction between adenosine A2A and metabotropic group 5 receptors in glutamatergic nerve terminals of the rat striatum

The anti‐Parkinsonian effect of glutamate metabotropic group 5 (mGluR5) and adenosine A2A receptor antagonists is believed to result from their ability to postsynaptically control the responsiveness of the indirect pathway that is hyperfunctioning in Parkinsons disease. mGluR5 and A2A antagonists are also neuroprotective in brain injury models involving glutamate excitotoxicity. Thus, we hypothesized that the anti‐Parkinsonian and neuroprotective effects of A2A and mGluR5 receptors might be related to their control of striatal glutamate release that actually triggers the indirect pathway. The A2A agonist, CGS21680 (1–30 nm) facilitated glutamate release from striatal nerve terminals up to 57%, an effect prevented by the A2A antagonist, SCH58261 (50 nm). The mGluR5 agonist, CHPG (300–600 μm) also facilitated glutamate release up to 29%, an effect prevented by the mGluR5 antagonist, MPEP (10 μm). Both mGluR5 and A2A receptors were located in the active zone and 57 ± 6% of striatal glutamatergic nerve terminals possessed both A2A and mGluR5 receptors, suggesting a presynaptic functional interaction. Indeed, submaximal concentrations of CGS21680 (1 nm) and CHPG (100 μm) synergistically facilitated glutamate release and the facilitation of glutamate release by 10 nm CGS21680 was prevented by 10 μm MPEP, whereas facilitation by 300 μm CHPG was prevented by 10 nm SCH58261. These results provide the first direct evidence that A2A 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 Parkinsons disease.

Clinical case: Differential diagnosis of idiopathic pulmonary fibrosis

BackgroundThe diagnosis of idiopathic pulmonary fibrosis can be quite challenging, even after careful clinical evaluation, imaging and pathological tests. This case report intends to demonstrate and discuss these difficulties, especially those concerning the differential diagnosis with chronic hypersensitivity pneumonitis.Case presentationA 58-year-old white male presented with shortness of breath, dry cough, fatigue and weight loss for two months. He was a former smoker and had regular exposure to a parakeet and poultry. Physical examination revealed bilateral basal crackles and chest imaging showed subpleural cystic lesions and traction bronchiectasis with a right side and upper level predominance. Auto-antibodies and IgG immunoglobulins to parakeet and fungal proteins were negative. Lung function tests displayed moderate restriction, low diffusion capacity and resting hypoxaemia. Bronchoalveolar lavage showed increased lymphocytes (28%) and neutrophils (12%) and surgical lung biopsy was compatible with a pattern of usual interstitial pneumonia. According to the possibility of either idiopathic pulmonary fibrosis or chronic hypersensitivity pneumonitis, treatment included prednisolone, azathioprine, acetylcysteine and avoidance of contact with the parakeet, but there was an unfavorable response and the patient was subsequently referred for lung transplant.ConclusionChronic hypersensitivity pneumonitis and idiopathic pulmonary fibrosis can present with the same clinical and radiological manifestations In this case, despite careful evaluation, no definite diagnosis could be achieved.

Effect of free radicals on adenosine A2A and dopamine D2 receptors in the striatum of young adult and aged rats

Parkinsons disease (PD) is a prevalent age-related motor dysfunction resulting from the hyperactivity of the indirect striatal pathway, which is controlled in an antagonistic manner by inhibitory dopamine D2 and facilitatory adenosine A(2A) receptors. Thus, dopamine precursors like l-DOPA are the standard therapy and A(2A) antagonists are now tested as anti-parkinsonians. Increased free radicals levels occur on aging and are proposed to be a contributing factor for PD. We now tested if free radicals affected A(2A) and D2 receptors in striatal membranes of young adult (2 months) and old (24 months) rats. The A(2A) receptor antagonist [3H]SCH 58261 bound to striatal membranes with a KD of 0.9 nM and a Bmax of 953 fmol/mg protein in young rats and with a KD of 0.8 nM and a Bmax of 725 fmol/mg protein in aged rats (24% decrease). The D2 receptor antagonist [3H]raclopride bound to striatal membranes with a KD of 4.0 nM and a Bmax of 598 fmol/mg protein in young rats and with a KD of 4.3 nM and a Bmax of 368 fmol/mg protein in aged rats (38% decrease). Exposure of striatal membranes to a free radical generation system (2 mM FeSO4 and 4 mM ascorbate) caused a similar decrease of [3H]SCH 58261 (35%) and [3H]raclopride (37%) binding in young adult rats but caused a greater decrease of [3H]SCH 58261 (49%) than of [3H]raclopride (20%) binding in aged rats. Thus, in aged rats, there is an unbalance of A(2A)/D2 receptor density favouring A(2A) receptors, which is restored on exposure to free radicals. This supports the hypothesis that the effectiveness of A(2A) receptor antagonists as anti-parkinsonians, demonstrated in young adult animals, may not be affected by a modified A(2A)/D2 receptor density in aged individuals suffering from exposure to increased free radical levels, as occurs in PD.

Organizing Pneumonia due to Actinomycosis: An Undescribed Association

Organizing pneumonia is a pathologic entity characterized by intra-alveolar buds of granulation tissue that can extend to the bronchiolar lumen. It is a non-specific finding reflecting a pattern of pulmonary response to aggression that can be cryptogenic or associated with several causes. Pulmonary actinomycosis is a rare infectious disease, of bacterial aetiology, and of difficult diagnosis. This disease usually causes non-specific respiratory symptoms and radiological findings, and the treatment is based on the use of antibiotics. The authors describe a clinical case of a 53-year-old male smoker (50 pack years), initially seen for complaints of right-sided chest pain and sub-febrile temperature. Imaging studies revealed a mass in the inferior right lobe and enlarged mediastinal lymph nodes. Empirical treatment with antibiotics caused partial and temporary improvement. Transthoracic biopsy revealed a pattern of organizing pneumonia with giant multinucleated cell granulomas. Repeat imaging studies revealed an enlargement of the pulmonary mass and therefore a right inferior lobectomy was performed. The pathologic study revealed a histological pattern of organizing pneumonia surrounding inflammatory bronchiectasis with a large number of Actinomyces colonies. To our knowledge there is presently no report in the literature of organizing pneumonia associated with Actinomyces infection.

Sobreposição de asma brônquica e DPOC

Immunoglobulin quantification showed an increase in total IgE levels (671 IU/mL), with no other abnormalities. Alpha-1 antitrypsin levels were normal. Respiratory function test results revealed moderately severe obstructive lung disease accompanied by inflation, moderately reduced alveolar-capillary diffusion, and mild type I respiratory failure. The patient had a negative bronchodilator response (Table 1). Her electrocardiogram was normal, and the results of the microbiological study of sputum were negative. The final diagnosis was uncontrolled bronchial asthma, pulmonary emphysema, diffuse bronchiectasis, and gastroesophageal reflux disease (GERD). The patient attributed her hypopharyngeal pain to the use of inhaled corticosteroids and therefore decided to discontinue the medication, having consequently shown improvement. She was started on esomeprazole, and salmeterol was replaced by indacaterol. Although this improved her pharyngeal and epigastric pain, she still had To the Editor:

Caffeine consumption and exacerbations of chronic obstructive pulmonary disease: Retrospective study

BACKGROUND The modulation of adenosine receptors has been proposed as new therapeutic target for chronic obstructive pulmonary disease, but studies in humans were negative. Caffeine is widely consumed and acts by non-selective modulation of these receptors, allowing for a non-interventional evaluation of the purinergic effects on COPD. We evaluated the effects of chronic caffeine consumption on the risk for COPD exacerbations. METHODS Retrospective study including patients with COPD. The total number of exacerbations during a three-year period and the mean daily caffeine consumption in the last twenty years were evaluated. A univariate and multiple regression analysis were performed for evaluation of the significant predictors of exacerbations. RESULTS A total of 90 patients were included. Most were males (82.2%) and had a mean forced expiratory volume in the first second (FEV1) of 57.0±17.1% predicted. The mean daily caffeine consumption was 149.7±140.9mg. There was no correlation between the mean caffeine consumption and exacerbations (p>0.05). DISCUSSION Our results suggest that caffeine has no significant effect on the frequency of COPD exacerbations. These conclusions are limited by the sample size and the retrospective nature of the study.

Poland syndrome and pneumothorax: the compelling evidence of an association

Poland Syndrome is a rare congenital deformity which mainly occurs sporadically but occasional familial cases have been reported. It is characterized by unilateral absence of pectoralis muscle, typically in association with other deformities of the ipsilateral chest wall and/or upper limbs. According to recent classifications, the pectoralis muscle anomaly alone is enough to establish diagnosis. It predominantly affects the right hemithorax (67-75%), with rare bilateral cases described. The most commonly accepted causal mechanism is related to disruption of blood supply through the subclavian artery during embryogenesis. Incidence varies from 1/70000 to 1/100000 live births, with a male to female ratio of 2-3 to 1. Due to mild or even nonexistent functional impairment, the condition is thought to be under-reported and underdiagnosed. Surgical correction is recommended in cases of significant functional or aesthetic impairment. We report the case of a 19 year-old male, admitted to the emergency room presenting with left-sided chest pain 24 hours after onset. He had no other complaints and there was no precipitating event, such as, trauma or infection.The patient was a non-smoker; with no relevant personal or family past medical history. Physical examination showed the patient to be tachycardic and slightly polypneic. Thoracic inspection showed hypoplasia of the left thoracic wall due to the underdevelopment of the left pectoralis muscle and decreased chest expansion. No other structural abnormalities were observed on the affected side of the torso. Also on the left hemithorax, there was hyperresonance to percussion and absent breath sounds on ausculation. Chest x-ray showed a large left lung pneumothorax; a chest tube was successfully placed with clinical improvement and total lung expansion. Thoracic computer tomography (Figures 1 and 2) revealed hypoplasia of the major pectoralis muscle confirming the diagnosis of Poland Syndrome and ruled out other abnormalities. There was full resolution of the pneumothorax and the chest tube was removed after four days.

Highlights from the 2018 European Respiratory Society Congress presentations on interstitial lung diseases

Interstitial lung diseases (ILDs) are a large and heterogeneous group of lung disorders characterized by primary involvement of the lung interstitium. Several studies point out their increasing incidence and global burden leading to a growing interest and massive literature production in the last few years.

Chronic coffee consumption and respiratory disease: A systematic review

The widespread consumption of coffee means that any biological effects from its use can lead to significant public health consequences. Chronic pulmonary diseases are extremely prevalent and responsible for one of every six deaths on a global level.

Severe ketorolac-induced asthma diagnosed by chest computed tomography

Aspirin-exacerbated respiratory disease (AERD) affects 15% of severe asthmatics and drug reactions cause 200,000 annual deaths in Europe. A 65-year-old lady presented to emergency for progressive abdominal pain. Her medical history included gallstones, asthma, rhinosinusitis and hypertension. She was regularly medicated with inhaled fluticasone, vilanterol and tiotropium, nasal budesonide, pantoprazole, oxazepam and perindopril. She reported partial asthma control and an exacerbation requiring admission to a respiratory ward 6 weeks before. On examination, there was right upper quadrant tenderness and no other changes. Blood tests were normal, and an ultrasound showed gallbladder stones with normal wall. Intravenous ketorolac led to prompt pain resolution. After 30 minutes she became severely dyspnoeic, with an O2 saturation of 85% on high flow O2. She had no breath sounds on the left lung, and there was no wheezing or prolonged expiration. A chest X-ray showed no pneumothorax and a computed tomography (CT) angiography was performed showing bilateral mucoid impaction and sub-segmental atelectasis. Continuous bronchodilation and systemic steroids led to gradual improving in the following 6 hours. After 9 days of admission on a respiratory ward she was discharged home with no symptoms and normal oxygenation. Importantly, she denied previous allergies to nonsteroidal anti-inflammatory drugs (NSAIDs) and had actually taken diclofenac and nimesulid before with no reactions. This report illustrates both an intravenous NSAID causing severe AERD, and how a chest CT may be instrumental for the diagnosis of life-threatening asthma.