Folia Microbiol (Praha). 2022 Mar 24. doi: 10.1007/s12223-022-00962-9. Online ahead of print.

ABSTRACT

Conversion to mucoid form is a crucial step in the pathogenesis of P. aeruginosa in burns and cystic fibrosis (CF) patients. Alginate is considered the major component of biofilm and is highly associated with the formation of mucoid biofilm in this species. Nonsteroid anti-inflammatory drugs (NSAIDs), including ibuprofen, have shown promising antibacterial and antibiofilm potential for bacterial pathogens. In this study, we aimed to evaluate the effect of ibuprofen on the expression of alginate synthetase (alg8), GDP-mannose dehydrogenase (algD), and alginate lyase (algL) genes in multiple drug-resistant (MDR) P. aeruginosa strains. The biofilm formation potential and the expression of alg8, algD, and algL among the bacteria treated with ibuprofen (at sub-inhibitory concentration) were investigated using the crystal violet staining and real-time PCR assays, respectively. The minimum inhibitory concentration of ibuprofen for the studied strains was determined 1024-2048 µg/mL. We observed that ibuprofen was able to reduce bacterial biofilm by 51-77%. Also, the expression of alg8, algD, and algL decreased by 32, 52, and 48%, respectively. The reduction of the genes responsible for alginate synthesis indicates promising antivirulece potential of ibuprofen to combat P. aeruginosa infection, especially in burns and CF patients. Our findings suggest that ibuprofen could be used to reduce the pathogenicity of P. aeruginosa that could be used in combination with antibiotics to treat drug-resistant infections.

PMID:35325409 | DOI:10.1007/s12223-022-00962-9

Toxins (Basel). 2022 Mar 18;14(3):225. doi: 10.3390/toxins14030225.

ABSTRACT

Vibrio cholerae uses cholera toxin (CT) to cause cholera, a severe diarrheal disease in humans that can lead to death within hours of the onset of symptoms. The catalytic activity of CT in target epithelial cells increases cellular levels of 3',5'-cyclic AMP (cAMP), leading to the activation of the cystic fibrosis transmembrane conductance regulator (CFTR), an apical ion channel that transports chloride out of epithelial cells, resulting in an electrolyte imbalance in the intestinal lumen and massive water loss. Here we report that when administered perorally, benzopyrimido-pyrrolo-oxazinedione, (R)-BPO-27), a potent small molecule inhibitor of CFTR, blocked disease symptoms in a mouse model for acute diarrhea caused by toxigenic V. cholerae. We show that both (R)-BPO-27 and its racemic mixture, (R/S)-BPO-27, are able to protect mice from CT-dependent diarrheal disease and death. Furthermore, we show that, consistent with the ability of the compound to block the secretory diarrhea induced by CT, BPO-27 has a measurable effect on suppressing the gut replication and survival of V. cholerae, including a 2010 isolate from Haiti that is representative of the most predominant 'variant strains' that are causing epidemic and pandemic cholera worldwide. Our results suggest that BPO-27 should advance to human Phase I studies that could further address its safety and efficacy as therapeutic or preventative drug intervention for diarrheal syndromes, including cholera, that are mediated by CFTR channel activation.

PMID:35324722 | DOI:10.3390/toxins14030225

Proc Natl Acad Sci U S A. 2022 Mar 29;119(13):e2121731119. doi: 10.1073/pnas.2121731119. Epub 2022 Mar 24.

ABSTRACT

SignificanceIn many lung diseases, increased amounts of and/or abnormal mucus impair mucociliary clearance, a key defense against inhaled and aspirated material. Submucosal glands lining cartilaginous airways secrete mucus strands that are pulled by cilia until they break free from the duct and sweep upward toward the larynx, carrying particulates. In cystic fibrosis (CF) pigs, progressive clearance of insufflated microdisks was repeatedly interrupted as microdisks abruptly recoiled. Aerosolizing a reducing agent to break disulfide bonds linking mucins ruptured mucus strands, freeing them from submucosal gland ducts and allowing cilia to propel them up the airways. These findings highlight the abnormally increased elasticity of CF mucus and suggest that agents that break disulfide bonds might have value in lung diseases with increased mucus.

PMID:35324331 | DOI:10.1073/pnas.2121731119

J Antimicrob Chemother. 2022 Mar 22:dkac084. doi: 10.1093/jac/dkac084. Online ahead of print.

ABSTRACT

BACKGROUND: Non-cystic fibrosis bronchiectasis (BE) is a chronic structural lung condition that facilitates chronic colonization by different microorganisms and courses with recurrent respiratory infections and frequent exacerbations. One of the main pathogens involved in BE is Pseudomonas aeruginosa.

OBJECTIVES: To determine the molecular mechanisms of resistance and the molecular epidemiology of P. aeruginosa strains isolated from patients with BE.

METHODS: A total of 43 strains of P. aeruginosa were isolated from the sputum of BE patients. Susceptibility to the following antimicrobials was analysed: ciprofloxacin, meropenem, imipenem, amikacin, tobramycin, aztreonam, piperacillin/tazobactam, ceftazidime, ceftazidime/avibactam, ceftolozane/tazobactam, cefepime and colistin. The resistance mechanisms present in each strain were assessed by PCR, sequencing and quantitative RT-PCR. Molecular epidemiology was determined by MLST. Phylogenetic analysis was carried out using the eBURST algorithm.

RESULTS: High levels of resistance to ciprofloxacin (44.19%) were found. Mutations in the gyrA, gyrB, parC and parE genes were detected in ciprofloxacin-resistant P. aeruginosa strains. The number of mutated QRDR genes was related to increased MIC. Different β-lactamases were detected: blaOXA50, blaGES-2, blaIMI-2 and blaGIM-1. The aac(3)-Ia, aac(3)-Ic, aac(6″)-Ib and ant(2″)-Ia genes were associated with aminoglycoside-resistant strains. The gene expression analysis showed overproduction of the MexAB-OprM efflux system (46.5%) over the other efflux system. The most frequently detected clones were ST619, ST676, ST532 and ST109.

CONCLUSIONS: Resistance to first-line antimicrobials recommended in BE guidelines could threaten the treatment of BE and the eradication of P. aeruginosa, contributing to chronic infection.

PMID:35323912 | DOI:10.1093/jac/dkac084

Ther Adv Respir Dis. 2022 Jan-Dec;16:17534666221086416. doi: 10.1177/17534666221086416.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) affects more than 80,000 people worldwide, having a considerable impact on the quality of life of patients and their caregivers, who assist patients with time-consuming treatment regimens. Despite this, a review of the available evidence has not been previously undertaken. This systematic literature review aimed to identify the humanistic and economic burdens of CF on caregivers.

METHODS: A systematic literature review was conducted, in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Publications reporting outcomes for the caregivers of people with CF, including utility data, health status, and occupational impact, were reviewed. Sources searched were Embase (OvidSP), Medline (PubMed), the Cochrane Database of Systematic Reviews, and the Epistemonikos database, from 2010 to March 2020. A subsequent search with updated terms identified articles up to April 2020. Electronic searches were supplemented by hand searches to capture all relevant literature.

RESULTS: A total of 889 articles reporting humanistic burden and 310 reporting economic burden were identified. Following full-text screening by two independent reviewers, 72 articles were included in the review, of which 65 and 17 reported data on humanistic and economic burdens, respectively, with 10 reporting on both. The reviewed literature covered several outcomes and identified multiple key findings: greater disease severity is associated with the reporting of greater caregiver burden and lower utility scores of quality of life; reduced patient lung function is associated with increased caregiver depression and anxiety; and caregiving causes significant occupational impact, with pulmonary exacerbations decreasing caregiver productivity by up to a third compared with the patient being in a 'well' state.

CONCLUSION: Findings from this systematic literature review highlight the substantial humanistic and economic burdens borne by the caregivers of people with CF. Future research would help to further inform on the link between disease severity and caregiver burden.

PMID:35323061 | DOI:10.1177/17534666221086416

Pediatr Pulmonol. 2022 Mar 23. doi: 10.1002/ppul.25903. Online ahead of print.

ABSTRACT

We report physiotherapy management of two patients with severe cystic fibrosis (CF) lung disease and upper limb deep vein thrombosis (DVT). These patients were admitted due to a pulmonary exacerbation. Following peripherally inserted central catheters they were diagnosed with an upper limb DVT. Due to their underlying lung disease, physiotherapy was mandatory for improvement. However, the DVT and anticoagulation treatment raised concerns for pulmonary emboli and hemoptysis. A framework for physiotherapy management in these patients, using a set of precautions and restrictions to maintain airway clearance while minimizing risk for pulmonary emboli and hemoptysis, was established. Using these set of instructions, the patients experienced no major adverse event while maintaining sufficient airway clearance to allow respiratory improvement. These precautions were continued until the upper limb DVTs resolved. To our knowledge there are currently no guidelines nor expert opinions available. Therefore, this framework can help guide physiotherapy management This article is protected by copyright. All rights reserved.

PMID:35322603 | DOI:10.1002/ppul.25903

Nature. 2022 Mar 23. doi: 10.1038/s41586-022-04543-1. Online ahead of print.

ABSTRACT

Membrane fusion triggered by Ca2+ is orchestrated by a conserved set of proteins to mediate synaptic neurotransmitter release, mucin secretion and other regulated exocytic processes1-4. For neurotransmitter release, the Ca2+ sensitivity is introduced by interactions between the Ca2+ sensor synaptotagmin and the SNARE complex5, and sequence conservation and functional studies suggest that this mechanism is also conserved for mucin secretion6. Disruption of Ca2+-triggered membrane fusion by a pharmacological agent would have therapeutic value for mucus hypersecretion as it is the major cause of airway obstruction in the pathophysiology of respiratory viral infection, asthma, chronic obstructive pulmonary disease and cystic fibrosis7-11. Here we designed a hydrocarbon-stapled peptide that specifically disrupts Ca2+-triggered membrane fusion by interfering with the so-called primary interface between the neuronal SNARE complex and the Ca2+-binding C2B domain of synaptotagmin-1. In reconstituted systems with these neuronal synaptic proteins or with their airway homologues syntaxin-3, SNAP-23, VAMP8, synaptotagmin-2, along with Munc13-2 and Munc18-2, the stapled peptide strongly suppressed Ca2+-triggered fusion at physiological Ca2+ concentrations. Conjugation of cell-penetrating peptides to the stapled peptide resulted in efficient delivery into cultured human airway epithelial cells and mouse airway epithelium, where it markedly and specifically reduced stimulated mucin secretion in both systems, and substantially attenuated mucus occlusion of mouse airways. Taken together, peptides that disrupt Ca2+-triggered membrane fusion may enable the therapeutic modulation of mucin secretory pathways.

PMID:35322233 | DOI:10.1038/s41586-022-04543-1

Sci Rep. 2022 Mar 23;12(1):4986. doi: 10.1038/s41598-022-08927-1.

ABSTRACT

In a number of chronic respiratory diseases e.g. cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), the production of viscous mucin reduces pulmonary function and represents an effective barrier to diffusion of inhaled therapies e.g. antibiotics. Here, a 2-compartment Transwell model was developed to study impaired diffusion of the antibiotic colistin across an artificial sputum (AS) matrix/medium and to quantify its antimicrobial activity against Pseudomonas aeruginosa NH57388A biofilms (alone and in combination with mucolytic therapy). High-performance liquid chromatography coupled with fluorescence detection (HPLC-FLD) revealed that the presence of AS medium significantly reduced the rate of colistin diffusion (> 85% at 48 h; p < 0.05). Addition of alginate oligosaccharide (OligoG CF-5/20) significantly improved colistin diffusion by 3.7 times through mucin-rich AS medium (at 48 h; p < 0.05). Increased diffusion of colistin with OligoG CF-5/20 was shown (using confocal laser scanning microscopy and COMSTAT image analysis) to be associated with significantly increased bacterial killing (p < 0.05). These data support the use of this model to study drug and small molecule delivery across clinically-relevant diffusion barriers. The findings indicate the significant loss of colistin and reduced effectiveness that occurs with mucin binding, and support the use of mucolytics to improve antimicrobial efficacy and lower antibiotic exposure.

PMID:35322119 | DOI:10.1038/s41598-022-08927-1

Eur Respir Rev. 2022 Mar 23;31(163):210173. doi: 10.1183/16000617.0173-2021. Print 2022 Mar 31.

ABSTRACT

OBJECTIVE: Imaging represents an important noninvasive means to assess cystic fibrosis (CF) lung disease, which remains the main cause of morbidity and mortality in CF patients. While the development of new imaging techniques has revolutionised clinical practice, advances have posed diagnostic and monitoring challenges. The authors aim to summarise these challenges and make evidence-based recommendations regarding imaging assessment for both clinicians and radiologists.

STUDY DESIGN: A committee of 21 experts in CF from the 10 largest specialist centres in Italy was convened, including a radiologist and a pulmonologist from each centre, with the overall aim of developing clear and actionable recommendations for lung imaging in CF. An a priori threshold of at least 80% of the votes was required for acceptance of each statement of recommendation.

RESULTS: After a systematic review of the relevant literature, the committee convened to evaluate 167 articles. Following five RAND conferences, consensus statements were developed by an executive subcommittee. The entire consensus committee voted and approved 28 main statements.

CONCLUSIONS: There is a need for international guidelines regarding the appropriate timing and selection of imaging modality for patients with CF lung disease; timing and selection depends upon the clinical scenario, the patient's age, lung function and type of treatment. Despite its ubiquity, the use of the chest radiograph remains controversial. Both computed tomography and magnetic resonance imaging should be routinely used to monitor CF lung disease. Future studies should focus on imaging protocol harmonisation both for computed tomography and for magnetic resonance imaging. The introduction of artificial intelligence imaging analysis may further revolutionise clinical practice by providing fast and reliable quantitative outcomes to assess disease status. To date, there is no evidence supporting the use of lung ultrasound to monitor CF lung disease.

PMID:35321929 | DOI:10.1183/16000617.0173-2021

Expert Rev Respir Med. 2022 Mar 23. doi: 10.1080/17476348.2022.2057951. Online ahead of print.

ABSTRACT

INTRODUCTION: Pseudomonas aeruginosa is a common respiratory pathogen that contributes to chronic pulmonary infection in individuals with cystic fibrosis. Guidelines recommend early intervention upon positive P. aeruginosa culture. Tobramycin has in vitro activity against Gram-negative bacteria, including P. aeruginosa, and TOBI Podhaler is indicated for the management of individuals with cystic fibrosis with P. aeruginosa infection. The dry powder inhaler formulation decreases the time required for treatment compared with nebulized solution and therefore may improve quality of life and adherence, which have a positive impact on disease progression.

AREAS COVERED: In this review, we discuss the safety and efficacy of tobramycin inhaled powder and provide insights into appropriate individuals who might benefit from a dry powder inhaler, keeping in mind that patient preference is an important consideration for therapy selection.

EXPERT OPINION: Providing a less burdensome alternative to delivering inhaled antibiotics that is more portable with a significantly shorter administration time may help improve adherence, and therefore improve outcomes. Continued development of new antibiotics to add to current regimens for eradication and control of airway microbiology, combined with more efficient delivery systems such as tobramycin inhaled powder, will help evolve the treatment of patients with CF.

PMID:35320051 | DOI:10.1080/17476348.2022.2057951

Rev Med Chil. 2021 Aug;149(8):1173-1181. doi: 10.4067/s0034-98872021000801173.

ABSTRACT

Exhaled Nitric Oxide fraction measurement is a new method for the evaluation of respiratory diseases. It has good correlation with airway inflammation and decreases with the administration of corticosteroids. It is useful as a complement for the diagnosis of asthma, Chronic Obstructive Pulmonary Disease, Cystic Fibrosis and Primary Ciliary Dyskinesia among other respiratory diseases that generate inflammation in the airway. Its assessment is easy, non-invasive, and safe, and the result is obtained immediately. It can be used routinely to evaluate the response and adherence to treatments. This article reviews the biology of Nitric Oxide, and the measurement, interpretation, and main clinical uses of Exhaled Nitric Oxide Fraction.

PMID:35319704 | DOI:10.4067/s0034-98872021000801173

J Gen Intern Med. 2022 Mar 22. doi: 10.1007/s11606-022-07468-7. Online ahead of print.

ABSTRACT

BACKGROUND: The per diem financial structure of hospice care may lead agencies to consider patient-level factors when weighing admissions.

OBJECTIVE: To investigate if treatment cost, disease complexity, and diagnosis are associated with hospice willingness to accept patients.

DESIGN: In this 2019 online survey study, individuals involved in hospice admissions decisions were randomized to view one of six hypothetical patient vignettes: "high-cost, high-complexity," "low-cost, high-complexity," and "low-cost, low-complexity" within two diseases: heart failure and cystic fibrosis. Vignettes included demographics, prognoses, goals, and medications with costs. Respondents indicated their perceived likelihood of acceptance to their hospice; if likelihood was <100%, respondents were asked the barriers to acceptance. We used bivariate tests to examine associations between demographic, clinical, and organizational factors and likelihood of acceptance.

PARTICIPANTS: Individuals involved in hospice admissions decisions MAIN MEASURES: Likelihood of acceptance to hospice care KEY RESULTS: N=495 (76% female, 53% age 45-64). Likelihoods of acceptance in cystic fibrosis were 79.8% (high-cost, high-complexity), 92.4% (low-cost, high-complexity), and 91.5% (low-cost, low-complexity), and in heart failure were 65.9% (high-cost, high-complexity), 87.3% (low-cost, high-complexity), and 96.6% (low-cost, low-complexity). For both heart failure and cystic fibrosis, respondents were less likely to accept the high-cost, high-complexity patient than the low-cost, high-complexity patient (65.9% vs. 87.3%, 79.8% vs. 92.4%, both p<0.001). For heart failure, respondents were less likely to accept the low-cost, high-complexity patient than the low-cost, low-complexity patient (87.3% vs. 96.6%, p=0.004). Treatment cost was the most common barrier for 5 of 6 vignettes.

CONCLUSIONS: This study suggests that patients receiving expensive and/or complex treatments for palliation may have difficulty accessing hospice.

PMID:35319086 | DOI:10.1007/s11606-022-07468-7

Pediatr Pulmonol. 2022 Mar 22. doi: 10.1002/ppul.25902. Online ahead of print.

ABSTRACT

Lobar collapse is a common complication in cystic fibrosis (CF) This article is protected by copyright. All rights reserved.

PMID:35318832 | DOI:10.1002/ppul.25902

Immunol Cell Biol. 2022 Mar 23. doi: 10.1111/imcb.12547. Online ahead of print.

ABSTRACT

A population of neutrophils recruited into cystic fibrosis (CF) airways is associated with proteolytic lung damage, exhibiting high expression of primary granule exocytosis marker CD63 and reduced phagocytic receptor CD16. Causative factors for this population are unknown, limiting intervention. Here we present a laboratory model to characterise responses of differentiated airway epithelium and neutrophils following respiratory infection. Paediatric primary airway epithelial cells were cultured at air liquid interface (ALI), challenged individually or in combination with rhinovirus and Pseudomonas aeruginosa, then apically washed with medical saline to sample epithelial infection milieus. Cytokine multiplex analysis revealed epithelial antiviral signals including IP-10 and RANTES increased with exclusive rhinovirus infection but were diminished if P. aeruginosa was also present. Pro-inflammatory signals IL-1α and β were dominant in P. aeruginosa infection milieus. Infection washes were also applied to a published model of neutrophil transmigration into the airways. Neutrophils migrating into bacterial and viral-bacterial co-infection milieus exhibited the in vivo CF phenotype of increased CD63 expression and reduced CD16 expression, while neutrophils migrating into milieus of rhinovirus infected or uninfected cultures did not. Individually, bacterial products LPS and fMLF and isolated cytokine signals only partially activated this phenotype, suggesting additional soluble factors in the infection microenvironment trigger primary granule release. Findings identify P. aeruginosa as a trigger of acute airway inflammation and neutrophil primary granule exocytosis, underscoring potential roles of airway microbes in prompting this neutrophil subset. Further studies are required to characterise microbes implicated in primary granule release, and identify potential therapeutic targets.

PMID:35318736 | DOI:10.1111/imcb.12547

BMC Pregnancy Childbirth. 2022 Mar 22;22(1):236. doi: 10.1186/s12884-022-04498-1.

ABSTRACT

BACKGROUND: Preparing for pregnancy and being in the best possible health before conception improves reproductive outcomes. For women living with a chronic non-communicable disease (NCD), pregnancy planning is essential to allow optimal disease control in preparation for pregnancy.

AIM: The aim was to review the literature relating to the pregnancy planning health information and service needs of women with NCDs.

METHOD: The MEDLINE (Ovid), Embase (Ovid), Emcare (Ovid), PsycINFO (Ovid), CINAHL and Scopus databases were searched. Studies were included if they were published in peer-reviewed English language journals between January 2010 and June 2020 and reported on the pregnancy planning health information and service needs of women with rheumatic diseases, asthma, cystic fibrosis, depression and/or anxiety, type 1 diabetes mellitus, epilepsy, or multiple sclerosis. Risk of bias was assessed using QualSyst. The characteristics of the studies were tabulated and summarised. Key findings of the included studies were analysed thematically using an inductive approach, where the study findings determined the themes. Findings are reported in a narrative synthesis.

RESULTS: The database searches yielded 8291 results, of which 4304 remained after duplicates were removed. After abstract screening 104 full-text papers were reviewed. Of these 15 met inclusion criteria and were included in analysis. The narrative synthesis of the included studies revealed six themes: 'Women with chronic conditions have unmet preconception health information needs', 'Women with chronic conditions want personalised preconception health information', 'Preferred sources of preconception health information', 'Learning from the experiences of other women', 'Improving preconception health discussions with health care professionals', and 'Women want holistic care'. These themes were consistent across all studies, highlighting the similarity of experiences and needs of women with different chronic conditions.

CONCLUSION: To improve pregnancy outcomes for women living with NCDs, health care providers need to ask women of reproductive age proactively and routinely about their pregnancy intentions and provide them with personalised advice on how to avoid unplanned pregnancy and be in optimal health when they wish to conceive. PROSPERO registration number CRD42020176308.

PMID:35317730 | DOI:10.1186/s12884-022-04498-1

World J Hepatol. 2022 Feb 27;14(2):411-419. doi: 10.4254/wjh.v14.i2.411.

ABSTRACT

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators significantly improve pulmonary function in patients with cystic fibrosis (CF) but the effect on hepatobiliary outcomes remains unknown. We hypothesized that CF patients on CFTR modulators would have a decreased incidence of cirrhosis compared to patients not on CFTR modulators or on ursodiol.

AIM: To investigate the effect of CFTR modulators on the development of cirrhosis in patients with CF.

METHODS: A retrospective analysis was performed using Truven MarketScan from January 2012 through December 2017 including all patients with a diagnosis of CF. Patients were excluded if they underwent a liver transplantation or if they had other etiologies of liver disease including viral hepatitis or alcohol use. Subjects were grouped by use of CFTR modulators, ursodiol, dual therapy, or no therapy. The primary outcome was development of cirrhosis. Kaplan-Meier curves estimated the incidence of cirrhosis and log-rank tests compared incidence curves between treatment groups.

RESULTS: A total of 7201 patients were included, of which 955 (12.6%) used a CFTR modulator, 529 (7.0%) used ursodiol, 105 (1.4%) used combination therapy, and 5612 (74.3%) used neither therapy. The incidence of cirrhosis was 0.1% at 1 year and 0.7% at 4 years in untreated patients, 5.9% and 10.1% in the Ursodiol group, and 1.0% and 1.0% in patients who received both therapies. No patient treated with CFTR modulators alone developed cirrhosis. Patients on CFTR modulators alone had lower cirrhosis incidence than untreated patients (P = 0.05), patients on Ursodiol (P < 0.001), and patients on dual therapy (P = 0.003). The highest incidence of cirrhosis was found among patients treated with Ursodiol alone, compared to untreated patients (P < 0.001) or patients on Ursodiol and CFTR modulators (P = 0.01).

CONCLUSION: CFTR modulators are associated with a reduction in the incidence of cirrhosis compared to other therapies in patients with CF.

PMID:35317183 | PMC:PMC8891668 | DOI:10.4254/wjh.v14.i2.411

World J Gastroenterol. 2022 Mar 7;28(9):918-932. doi: 10.3748/wjg.v28.i9.918.

ABSTRACT

BACKGROUND: Intestinal ischemia/reperfusion (I/R) injury is a fatal syndrome that occurs under many clinical scenarios. The apoptosis of intestinal cells caused by ischemia can cause cell damage and provoke systemic dysfunction during reperfusion. However, the mechanism of I/R-induced apoptosis remains unclear. Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated chloride channel. Few researchers have paid attention to its role in intestinal I/R injury, or the relationship between CFTR and intestinal apoptosis induced by hypoxia/reoxygenation (H/R).

AIM: To investigate the effects of CFTR on I/R-induced intestinal apoptosis and its underlying molecular mechanisms.

METHODS: An intestinal I/R injury model was established in mice with superior mesenteric artery occlusion, and Caco2 cells were subjected to H/R for the simulation of I/R in vivo.

RESULTS: The results suggested that CFTR overexpression significantly increased the Caco2 cell viability and decreased cell apoptosis induced by the H/R. Interestingly, we found that the translocation of p65, an NF-κB member, from the cytoplasm to the nucleus after H/R treatment can be reversed by the overexpression of CFTR, the NF-κB P65 would return from the nucleus to the cytoplasm as determined by immunostaining. We also discovered that CFTR inhibited cell apoptosis in the H/R-treated cells, and this effect was significantly curbed by the NF-κB activator BA, AKT inhibitor GSK690693 and the PI3K inhibitor LY294002. Moreover, we demonstrated that CFTR overexpression could reverse the decreased PI3K/AKT expression induced by the I/R treatment in vivo or H/R treatment in vitro.

CONCLUSION: The results of the present study indicate that the overexpression of CFTR protects Caco2 cells from H/R-induced apoptosis; furthermore, it also inhibits H/R-induced apoptosis through the PI3K/AKT/NF-κB signaling pathway in H/R-treated Caco2 cells and intestinal tissues.

PMID:35317058 | PMC:PMC8908288 | DOI:10.3748/wjg.v28.i9.918

Bull Math Biol. 2022 Mar 22;84(5):54. doi: 10.1007/s11538-022-01006-6.

ABSTRACT

As antibiotic resistance grows more frequent for common bacterial infections, alternative treatment strategies such as phage therapy have become more widely studied in the medical field. While many studies have explored the efficacy of antibiotics, phage therapy, or synergistic combinations of phages and antibiotics, the impact of virus competition on the efficacy of antibiotic treatment has not yet been considered. Here, we model the synergy between antibiotics and two viral types, temperate and chronic, in controlling bacterial infections. We demonstrate that while combinations of antibiotic and temperate viruses exhibit synergy, competition between temperate and chronic viruses inhibits bacterial control with antibiotics. In fact, our model reveals that antibiotic treatment may counterintuitively increase the bacterial load when a large fraction of the bacteria are antibiotic resistant, and both chronic and temperate phages are present.

PMID:35316421 | DOI:10.1007/s11538-022-01006-6

Microbiol Spectr. 2022 Mar 22:e0274021. doi: 10.1128/spectrum.02740-21. Online ahead of print.

ABSTRACT

Extensively drug-resistant Pseudomonas aeruginosa (XDRPA) infection is a significant public health threat due to a lack of effective therapeutic options. New β-lactam-β-lactamase inhibitor combinations, including ceftazidime-avibactam (CZA), have shown a high resistance rate to XDRPA. This study was therefore conducted to describe the underlying genomic mechanism of resistance for CZA nonsusceptible XDRPA strains that are non-metallo-β-lactamase (MBL) producers as well as to examine synergism of CZA and other antipseudomonal agents. Furthermore, the synergistic antibacterial activity of the most effective antimicrobial combination against non-MBL-producing XDRPA was evaluated through in vitro experiments. The resistance profiles of 15 CZA-resistant XDRPA strains isolated from clinical specimens in China-Japan Friendship Hospital between January 2017 to December 2020 were obtained by whole-genome sequencing (WGS) analysis. MBL genes blaIMP-1 and blaIMP-45 were found in 2 isolates (2/15, 13.3%); the other underlying CZA-resistance mechanisms involved the decreased OprD porin (13/13), blaAmpC overexpression (8/13) or mutation (13/13), and upregulated efflux pumps (13/13). CZA-imipenem (CZA-IPM) combination was identified to be the most effective against non-MBL-producing XDRPA according to the results of WGS analysis and combined antimicrobial susceptibility tests, with an approximately 16.62-fold reduction in MICs compared to CZA alone. Furthermore, the results of checkerboard analysis and growth curve displayed the synergistic antimicrobial activity of CZA and IPM against non-MBL-producing XDRPA. Electron microscopy also revealed that CZA-IPM combination might lead to more cellular structural alterations than CZA or IPM alone. This study suggested that the CZA-IPM combination has potential for non-MBL-producing XDRPA with blaAmpC overexpression or mutation, decreased OprD porin, and upregulated efflux pumps. IMPORTANCE Handling the infections by extensively drug-resistant Pseudomonas aeruginosa (XDRPA) strains is challenging due to their complicated antibiotic resistance mechanisms in immunosuppressed patients with pulmonary diseases (e.g., cystic fibrosis, chronic obstructive pulmonary disease, and lung transplant), ventilator-associated pneumonia, and bloodstream infections. The current study suggested the potentiality of the ceftazidime-avibactam-imipenem combination against XDRPA with blaAmpC overexpression or mutation, decreased OprD porin, and/or upregulated efflux pumps. Our findings indicate the necessity of combined drug sensitivity tests against XDRPA and also lay a foundation for the development of prevention, control, and treatment strategies in XDRPA infections.

PMID:35315696 | DOI:10.1128/spectrum.02740-21

Acta Biomed. 2022 Mar 14;93(1):e2022021. doi: 10.23750/abm.v93i1.10731.

ABSTRACT

BACKGROUND: Anxiety and depression may affect asthma control. Previously, it has been reported that the hospital anxiety depression scale (HADS) questionnaire was fruitful in the management of adolescents with asthma. This study compared the scores of two different questionnaires, namely the Childhood Anxiety Sensitivity Index (CASI) and Children's Depression Inventory (CDI), with asthma control level and lung function in asthmatic adolescents, evaluated in a real-life setting.

METHODS: A group of adolescents with asthma was consecutively enrolled. Asthma was diagnosed according to the GINA document, and consistently the symptom control grade was assessed. The adolescents completed the CASI, CDI, and Asthma Control Test (ACT) questionnaires. Visual Analogue Scale (VAS) for asthma symptoms perception and doctor's asthma control evaluation were considered. Lung function and clinical characteristics were also assessed.

RESULTS: Totally, 87 asthmatic adolescents (60 males, 27 females, median age 14.2 years) were evaluated. 16.1% of asthmatic adolescents had anxious symptoms detected by CASI, and 11.5% depressive symptoms revealed by CDI. High scores of both CASI and CDI were significantly associated with uncontrolled asthma (p= 0.013 and 0.043, respectively).

CONCLUSIONS: This study showed that anxiety and depression affected asthma control. Thus, in clinical practice, the psychological assessment could be included in asthmatic adolescents' asthma work-up.

PMID:35315428 | DOI:10.23750/abm.v93i1.10731