E-NTPDases in human airways: Regulation and relevance for chronic lung diseases

Chronic obstructive lung diseases are characterized by the inability to prevent bacterial infection and a gradual loss of lung function caused by recurrent inflammatory responses. In the past decade, numerous studies have demonstrated the importance of nucleotide-mediated bacterial clearance. Their interaction with P2 receptors on airway epithelia provides a rapid ‘on-and-off’ signal stimulating mucus secretion, cilia beating activity and surface hydration. On the other hand, abnormally high ATP levels resulting from damaged epithelia and bacterial lysis may cause lung edema and exacerbate inflammatory responses. Airway ATP concentrations are regulated by ecto nucleoside triphosphate diphosphohydrolases (E-NTPDases) which are expressed on the mucosal surface and catalyze the sequential dephosphorylation of nucleoside triphosphates to nucleoside monophosphates (ATP → ADP → AMP). The common bacterial product, Pseudomonas aeruginosa lipopolysaccharide (LPS), induces an acute reduction in azide-sensitive E-NTPDase activities, followed by a sustained increase in activity as well as NTPDase 1 and NTPDase 3 expression. Accordingly, chronic lung diseases, including cystic fibrosis (CF) and primary ciliary dyskinesia, are characterized by higher rates of nucleotide elimination, azide-sensitive E-NTPDase activities and expression. This review integrates the biphasic regulation of airway E-NTPDases with the function of purine signaling in lung diseases. During acute insults, a transient reduction in E-NTPDase activities may be beneficial to stimulate ATP-mediated bacterial clearance. In chronic lung diseases, elevating E-NTPDase activities may represent an attempt to prevent P2 receptor desensitization and nucleotide-mediated lung damage

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Vampires in the village Žrnovo on the island of Korčula: following an archival document from the 18th century

Središnja tema rada usmjerena je na raščlambu spisa pohranjenog u Državnom arhivu u Mlecima (fond: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) koji se odnosi na događaj iz 1748. godine u korčulanskom selu Žrnovo, kada su mještani – vjerujući da su se pojavili vampiri – oskvrnuli nekoliko mjesnih grobova. U radu se podrobno iznose osnovni podaci iz spisa te rečeni događaj analizira u širem društvenom kontekstu i prate se lokalna vjerovanja.The main interest of this essay is the analysis of the document from the State Archive in Venice (file: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) which is connected with the episode from 1748 when the inhabitants of the village Žrnove on the island of Korčula in Croatia opened tombs on the local cemetery in the fear of the vampires treating. This essay try to show some social circumstances connected with this event as well as a local vernacular tradition concerning superstitions

O espectro clínico e radiológico da pneumonia em organização: análise retrospectiva de 38 casos Clinical and radiographic spectrum of organizing pneumonia: retrospective analysis of 38 cases

A pneumonia em organização, acompanhada ou não de bronquiolite obliterante, é uma condição anatomopatológica pulmonar específica com uma grande variedade de apresentações clínicas e radiológicas. A pneumonia em organização pode ser idiopática ou secundária a várias doenças, incluindo infecções e drogas. Objetivos: Descrever as manifestações clínicas, dados radiológicos e espirométricos de pacientes com pneumonia em organização. Métodos: Análise retrospectiva de pacientes com o diagnóstico de pneumonia em organização. Resultados: 38 pacientes foram incluídos na análise. Quatorze apresentavam também condições clínicas relacionadas à pneumonia em organização, e estes mais freqüentemente apresentaram infiltração pulmonar difusa (três de quatro casos) e bronquiolite obliterante associada (57% vs. 20%, p = 0,05). Dos 13 pacientes com bronquiolite obliterante associada apenas um era assintomático e dois apresentavam lesões localizadas (15%). De oito pacientes assintomáticos com lesões localizadas, nenhum possuía bronquiolite obliterante associada, e a apresentação radiológica freqüentemente mimetizou carcinoma brônquico. A espirometria de modo geral não contribuiu sobremaneira para o diagnóstico, provavelmente devido à alta prevalência de tabagismo na amostra. Conclusões: A pneumonia em organização possui apresentação clínica e radiológica variada. Fatores que sugerem a ausência de bronquiolite obliterante são a ausência de sintomas e lesões radiológicas localizadas, e esta forma da doença mais freqüentemente deve ser diferenciada de carcinoma brônquico na prática clínica.<br>Organizing pneumonia, whether or not accompanied by bronchiolitis obliterans, is a specific anatomicopathological condition of the lungs that can present in a variety of clinical and radiographic ways. It can be either idiopathic or secondary to a number of diseases, including infection and drugs. Objectives: To describe the clinical manifestations, radiographic and spirometric data seen in patients with organizing pneumonia. Methods: Retrospective analysis of patients with a diagnosis of organizing pneumonia. Results: 38 patients were included in the analysis. Fourteen also had clinical conditions related to organizing pneumonia, and they presented more frequently with diffuse pulmonary infiltrates (three of four cases) and associated bronchiolitis obliterans (57% vs. 20%, p = 0,05). Of the 13 patients with bronchiolitis obliterans, only one was asymptomatic and two had localized lesions (15%). Of the eight asymptomatic patients with localized lesions, no one had associated bronchiolitis obliterans, and the radiographic appearance often resembled bronchial carcinoma. Spirometry was generally of little value to diagnosis, probably because of the high prevalence of smoking in the sample. Conclusion: The clinical and radiographic presentation of organizing pneumonia is variable. Factors that suggest the absence of coexisting bronchiolitis obliterans are the absence of symptoms and localized radiographic lesions, and this form of the disease has to be more often differentiated from bronchial carcinoma in clinical practice

The long non-coding RNA NEAT1 is responsive to neuronal activity and is associated with hyperexcitability states

Despite their abundance, the molecular functions of long non-coding RNAs in mammalian nervous systems remain poorly understood. Here we show that the long non-coding RNA, NEAT1, directly modulates neuronal excitability and is associated with pathological seizure states. Specifically, NEAT1 is dynamically regulated by neuronal activity in vitro and in vivo, binds epilepsy-associated potassium channel-interacting proteins including KCNAB2 and KCNIP1, and induces a neuronal hyper-potentiation phenotype in iPSC-derived human cortical neurons following antisense oligonucleotide knockdown. Next generation sequencing reveals a strong association of NEAT1 with increased ion channel gene expression upon activation of iPSC-derived neurons following NEAT1 knockdown. Furthermore, we show that while NEAT1 is acutely down-regulated in response to neuronal activity, repeated stimulation results in NEAT1 becoming chronically unresponsive in independent in vivo rat model systems relevant to temporal lobe epilepsy. We extended previous studies showing increased NEAT1 expression in resected cortical tissue from high spiking regions of patients suffering from intractable seizures. Our results indicate a role for NEAT1 in modulating human neuronal activity and suggest a novel mechanistic link between an activity-dependent long non-coding RNA and epilepsy