J Clin Transl Endocrinol. 2021 Mar;23:100253. doi: 10.1016/j.jcte.2021.100253. Epub 2021 Mar 9.

ABSTRACT

Coronavirus disease 2019 (COVID-19) was declared a pandemic on March 11, 2020. In efforts to reduce the risk of transmission, telehealth visits for routine care has significantly increased in the United States. Cystic fibrosis patients have been categorized as a highly vulnerable population to COVID-19 infection. Cystic Fibrosis centers are rapidly assessing and responding to the pandemic to ensure the safety of CF patients. At our Cleveland Clinic Cystic Fibrosis center, we transitioned outpatient clinics to a virtual care model in March 2020. Here, we report the changes that were implemented to optimize diabetes management in CF patients through telehealth during the COVID-19 crisis.

PMID:33723506 | PMC:PMC7942190 | DOI:10.1016/j.jcte.2021.100253

Proc Natl Acad Sci U S A. 2021 Mar 23;118(12):e2022012118. doi: 10.1073/pnas.2022012118.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic human pathogen that develops difficult-to-treat biofilms in immunocompromised individuals, cystic fibrosis patients, and in chronic wounds. P. aeruginosa has an arsenal of physiological attributes that enable it to evade standard antibiotic treatments, particularly in the context of biofilms where it grows slowly and becomes tolerant to many drugs. One of its survival strategies involves the production of the redox-active phenazine, pyocyanin, which promotes biofilm development. We previously identified an enzyme, PodA, that demethylated pyocyanin and disrupted P. aeruginosa biofilm development in vitro. Here, we asked if this protein could be used as a potential therapeutic for P. aeruginosa infections together with tobramycin, an antibiotic typically used in the clinic. A major roadblock to answering this question was the poor yield and stability of wild-type PodA purified from standard Escherichia coli overexpression systems. We hypothesized that the insufficient yields were due to poor packing within PodA's obligatory homotrimeric interfaces. We therefore applied the protein design algorithm, AffiLib, to optimize the symmetric core of this interface, resulting in a design that incorporated five mutations leading to a 20-fold increase in protein yield from heterologous expression and purification and a substantial increase in stability to environmental conditions. The addition of the designed PodA with tobramycin led to increased killing of P. aeruginosa cultures under oxic and hypoxic conditions in both the planktonic and biofilm states. This study highlights the potential for targeting extracellular metabolites to assist the control of P. aeruginosa biofilms that tolerate conventional antibiotic treatment.

PMID:33723058 | DOI:10.1073/pnas.2022012118

Respir Med. 2021 Mar 6;180:106355. doi: 10.1016/j.rmed.2021.106355. Online ahead of print.

ABSTRACT

Non-pharmacological interventions and tracing-testing strategy proved insufficient to reduce SARS-CoV-2 spreading worldwide. Several vaccines with different mechanisms of action are currently under development. This review describes the potential target antigens evaluated for SARS-CoV-2 vaccine in the context of both conventional and next-generation platforms. We reported experimental data from phase-3 trials with a focus on different definitions of efficacy as well as factors affecting real-life effectiveness of SARS-CoV-2 vaccination, including logistical issues associated to vaccine availability, delivery, and immunization strategies. On this background, new variants of SARS-CoV-2 are discussed. We also provided a critical view on vaccination in special populations at higher risk of infection or severe disease as elderly people, pregnant women and immunocompromised patients. A final paragraph addresses safety on the light of the unprecedented reduction of length of the vaccine development process and faster authorization.

PMID:33721697 | DOI:10.1016/j.rmed.2021.106355

PLoS Pathog. 2021 Mar 15;17(3):e1009418. doi: 10.1371/journal.ppat.1009418. Online ahead of print.

ABSTRACT

Burkholderia multivorans is a member of the Burkholderia cepacia complex (Bcc), notorious for its pathogenicity in persons with cystic fibrosis. Epidemiological surveillance suggests that patients predominantly acquire B. multivorans from environmental sources, with rare cases of patient-to-patient transmission. Here we report on the genomic analysis of thirteen isolates from an endemic B. multivorans strain infecting four cystic fibrosis patients treated in different pediatric cystic fibrosis centers in Belgium, with no evidence of cross-infection. All isolates share an identical sequence type (ST-742) but whole genome analysis shows that they exhibit peculiar patterns of genomic diversity between patients. By combining short and long reads sequencing technologies, we highlight key differences in terms of small nucleotide polymorphisms indicative of low rates of adaptive evolution within patient, and well-defined, hundred Kbps-long segments of high enrichment in mutations between patients. In addition, we observed large structural genomic variations amongst the isolates which revealed different plasmid contents, active roles for transposase IS3 and IS5 in the deactivation of genes, and mobile prophage elements. Our study shows limited within-patient B. multivorans evolution and high between-patient strain diversity, indicating that an environmental microdiverse reservoir must be present for this endemic strain, in which active diversification is taking place. Furthermore, our analysis also reveals a set of 30 parallel adaptations across multiple patients, indicating that the specific genomic background of a given strain may dictate the route of adaptation within the cystic fibrosis lung.

PMID:33720991 | DOI:10.1371/journal.ppat.1009418

Microb Genom. 2021 Mar 15. doi: 10.1099/mgen.0.000511. Online ahead of print.

ABSTRACT

The Liverpool epidemic strain (LES) is an important transmissible clonal lineage of Pseudomonas aeruginosa that chronically infects the lungs of people with cystic fibrosis (CF). Previous studies have focused on the genomics of the LES in a limited number of isolates, mostly from one CF centre in the UK, and from studies highlighting identification of the LES in Canada. Here we significantly extend the current LES genome database by genome sequencing 91 isolates from multiple CF centres across the UK, and we describe the comparative genomics of this large collection of LES isolates from the UK and Canada. Phylogenetic analysis revealed that the 145 LES genomes analysed formed a distinct clonal lineage when compared with the wider P. aeruginosa population. Notably, the isolates formed two clades: one associated with isolates from Canada, and the other associated with UK isolates. Further analysis of the UK LES isolates revealed clustering by clinic geography. Where isolates clustered closely together, the association was often supported by clinical data linking isolates or patients. When compared with the earliest known isolate, LESB58 (from 1988), many UK LES isolates shared common loss-of-function mutations, such as in genes gltR and fleR. Other loss-of-function mutations identified in previous studies as common adaptations during CF chronic lung infections were also identified in multiple LES isolates. Analysis of the LES accessory genome (including genomic islands and prophages) revealed variations in the carriage of large genomic regions, with some evidence for shared genomic island/prophage complement according to clinic location. Our study reveals divergence and adaptation during the spread of the LES, within the UK and between continents.

PMID:33720817 | DOI:10.1099/mgen.0.000511

J Chem Inf Model. 2021 Mar 15. doi: 10.1021/acs.jcim.0c01207. Online ahead of print.

ABSTRACT

Cystic Fibrosis (CF) is caused by mutations to the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channel. CFTR is composed of two membrane spanning domains, two cytosolic nucleotide-binding domains (NBD1 and NBD2) and a largely unstructured R-domain. Multiple CF-causing mutations reside in the NBDs and some are known to compromise the stability of these domains. The ability to predict the effect of mutations on the stability of the cytosolic domains of CFTR and to shed light on the mechanisms by which they exert their effect is therefore important in CF research. With this in mind, we have predicted the effect on domain stability of 59 mutations in NBD1 and NBD2 using 15 different algorithms and evaluated their performances via comparison to experimental data using several metrics including the correct classification rate (CCR), and the squared Pearson correlation (R2) and Spearman's correlation (ρ) calculated between the experimental ΔTm values and the computationally predicted ΔΔG values. Overall, the best results were obtained with FoldX and Rosetta. For NBD1 (35 mutations), FoldX provided R2 and ρ values of 0.64 and -0.71, respectively, with an 86% correct classification rate (CCR). For NBD2 (24 mutations), FoldX R2, ρ, and CCR were 0.51, -0.73, and 75%, respectively. Application of the Rosetta high-resolution protocol (Rosetta_hrp) to NBD1 yielded R2, ρ, and CCR of 0.64, -0.75, and 69%, respectively, and for NBD2 yielded R2, ρ, and CCR of 0.29, -0.27, and 50%, respectively. The corresponding numbers for the Rosetta's low-resolution protocol (Rosetta_lrp) were R2 = 0.47, ρ = -0.69, and CCR = 69% for NBD1 and R2 = 0.27, ρ = -0.24, and CCR = 63% for NBD2. For NBD1, both algorithms suggest that destabilizing mutations suffer from destabilizing vdW clashes, whereas stabilizing mutations benefit from favorable H-bond interactions. Two triple consensus approaches based on FoldX, Rosetta_lpr, and Rosetta_hpr were attempted using either "majority-voting" or "all-voting". The all-voting consensus outperformed the individual predictors, albeit on a smaller data set. In summary, our results suggest that the effect of mutations on the stability of CFTR's NBDs could be largely predicted. Since NBDs are common to all ABC transporters, these results may find use in predicting the effect and mechanism of the action of multiple disease-causing mutations in other proteins.

PMID:33720715 | DOI:10.1021/acs.jcim.0c01207

J Pediatr Gastroenterol Nutr. 2021 Feb 22. doi: 10.1097/MPG.0000000000003090. Online ahead of print.

ABSTRACT

OBJECTIVES AND STUDY: There are a large interobserver variability in evaluating mucosal lesions of inflammatory bowel disease (IBD), especially in pediatric patients. This multicenter prospective observational study aims to evaluate interobserver agreement (IOA) among pediatric endoscopists in assigning validated IBD endoscopic scores in children.

METHODS: Fifteen videos of follow-up ileocolonoscopies in children with IBD were recorded and selected as cases. Eleven pediatric endoscopists from different centers blindly evaluated all videos and calculated scores: either Ulcerative Colitis Endoscopic Index of Severity (UCEIS) or simple endoscopic score for Crohn's Disease (SES-CD). Scores from all reviewer were compared in order to calculate IOA for general videos and specific sections. Scores from an expert adult reader were used to calculate possible reviewer's characteristics affecting scores reliability.

RESULTS: Intraclass correlation was 0.298 (95% CI: 0.13-0.55) for UC and 0.266 (0.11-0.52) for CD. When a disease activity categorization was adopted (remission, mild, moderate, severe activity) Fleiss' kappa coefficient was 0.408 (0.29-0.53) for UC and 0.552 (0.43-0.73) for CD. When stratified by item, vascular pattern of UC was the most reliable item IC: 0.624 (0.321-0.854). In multivariable analysis none of the reviewer's characteristics affected the readers' errors.

CONCLUSION: This multicenter study shows low agreement among pediatric endoscopists in evaluating endoscopic scores in children with IBD. By using disease activity categorization, agreement slightly increased, mostly for CD. All readers showed a low-grade concordance with the expert adult gastroenterologist's evaluations. Future specific training programs should be considered to increase interobserver agreement in using IBD endoscopic activity scores.

PMID:33720096 | DOI:10.1097/MPG.0000000000003090

Int J Pediatr Adolesc Med. 2021 Mar;8(1):25-28. doi: 10.1016/j.ijpam.2019.12.002. Epub 2019 Dec 10.

ABSTRACT

INTRODUCTION: Cystic fibrosis (CF) has been reported before in Saudi Arabia and the Gulf area. It has been found that screening for 10 most common cystic fibrosis transmembrane conductance regulator (CFTR) mutations can detect 80% of positive CFTR cases.

OBJECTIVES: To determine the geographic distribution of the most common CFTR variants in 5 regions of Saudi Arabia.

METHODOLOGY: A retrospective chart review of all CFTR variants conducted from January 1, 1992 to December 1, 2017.

RESULTS: The ten most common CFTR mutations in the Saudi population were as follows: p.Gly473GlufsX54 (17%), p.Phe508del (12%), p.Ile1234Val (12%), 3120+1G > A (11%), 711+1G > T (9%), p.His139Leu (6%), p.Gln637Hisfs (5%), p.Ser549Arg (3%), p.N1303K (3%), and delExon19-21 (2%) along with other variants 79 (20%). In terms of the highest frequency, the c.2988+1G > A (3120+1G > A) variant was found in the eastern province (7.3%) of Saudi Arabia, the c.1418delG (p.Gly473GlufsX54) variant in the northern province (6.8%), the c.579+1G > T (711+1G > T) variant in the southern province (4.8%), the c.3700A > G (p.Ile1234Val) variant in the central province (4.8%), and c.1521_1523delCTT (p.Phe508del) variant in the western province (4.3%).

CONCLUSION: The eastern and the northern provinces have the highest prevalence of CF, with the c.2988+1G > A (3120+1G > A) and c.1418delG (p.Gly473GlufsX54) variants showing the highest distribution in the Saudi CF population, which may reflect the effect of consanguinity within the same tribe. Proper family screening and counseling should be emphasized.

PMID:33718573 | PMC:PMC7922840 | DOI:10.1016/j.ijpam.2019.12.002

ERJ Open Res. 2021 Mar 8;7(1):00513-2020. doi: 10.1183/23120541.00513-2020. eCollection 2021 Jan.

ABSTRACT

Lung damage in cystic fibrosis (CF) is strongly associated with lower airway infections. Early treatment of Pseudomonas aeruginosa is recommended. Pathogen detection requires sampling of lower airway secretions, which remains a challenge in nonexpectorating patients. Our hypothesis was that chest physiotherapy would improve the quality of airway secretion samples and increase the rates of pathogens detected in nonexpectorating patients. This prospective multicentre study compared three successive methods for sampling airway secretions applied through the same session: 1) an oropharyngeal swab (OP), 2) a chest physiotherapy session followed by a provoked cough to obtain sputum (CP-SP) and 3) a second oropharyngeal swab collected after chest physiotherapy (CP-OP). Haemophilus influenzae, Staphylococcus aureus and P. aeruginosa growth cultures were assessed. Accuracy tests and an equivalence test were performed to compare the three successive methods of collection. 300 nonexpectorating children with CF were included. P. aeruginosa was detected cumulatively in 56 (18.9%) children, and according to the different collection methods in 28 (9.8%), 37 (12.4%) and 44 (14.7%) children by using OP, CP-OP and CP-SP, respectively. Compared with OP, the increased detection rate was +22% for CP-OP (p=0.029) and +57% for CP-SP (p=0.003). CP-SP had the best positive predictive value (86.3%) and negative predictive value (96.0%) for P. aeruginosa compared with the overall detection. The results of this adequately powered study show differences in the rates of pathogens detected according to the sampling method used. Chest physiotherapy enhanced detection of P. aeruginosa in nonexpectorating children with CF.

PMID:33718497 | PMC:PMC7938055 | DOI:10.1183/23120541.00513-2020

ERJ Open Res. 2021 Mar 8;7(1):00706-2020. doi: 10.1183/23120541.00706-2020. eCollection 2021 Jan.

ABSTRACT

In smokers with preserved spirometry, D LCO is associated with ventilation inhomogeneity arising from peripheral airways. Measurement of D LCO to screen for early lung function abnormalities in smokers may be suboptimal and could be replaced by MBW. https://bit.ly/3nLmgg1.

PMID:33718489 | PMC:PMC7938046 | DOI:10.1183/23120541.00706-2020

Front Pediatr. 2021 Feb 25;9:635719. doi: 10.3389/fped.2021.635719. eCollection 2021.

ABSTRACT

As Cystic Fibrosis (CF) treatment advances, research evidence has highlighted the value and applicability of Lung Clearance Index and Cardiopulmonary Exercise Testing as endpoints for clinical trials. In the context of these new endpoints for CF trials, we have explored the use of these two test outcomes for routine CF care. In this review we have presented the use of these methods in assessing disease severity, disease progression, and the efficacy of new interventions with considerations for future research.

PMID:33718306 | PMC:PMC7946844 | DOI:10.3389/fped.2021.635719

J Aerosol Sci. 2021 Mar;153:105692. doi: 10.1016/j.jaerosci.2020.105692. Epub 2020 Oct 14.

ABSTRACT

While dry powder aerosol formulations offer a number of advantages, their use in children is often limited due to poor lung delivery efficiency and difficulties with consistent dry powder inhaler (DPI) usage. Both of these challenges can be attributed to the typical use of adult devices in pediatric subjects and a lack of pediatric-specific DPI development. In contrast, a number of technologies have recently been developed or progressed that can substantially improve the efficiency and reproducibility of DPI use in children including: (i) nose-to-lung administration with small particles, (ii) active positive-pressure devices, (iii) structures to reduce turbulence and jet momentum, and (iv) highly dispersible excipient enhanced growth particle formulations. In this study, these technologies and their recent development are first reviewed in depth. A case study is then considered in which these technologies are simultaneously applied in order to enable the nose-to-lung administration of dry powder aerosol to children with cystic fibrosis (CF). Using a combination of computational fluid dynamics (CFD) analysis and realistic in vitro experiments, device performance, aerosol size increases and lung delivery efficiency are considered for pediatric-CF subjects in the age ranges of 2-3, 5-6 and 9-10 years old. Results indicate that a new 3D rod array structure significantly improves performance of a nasal cannula reducing interface loss by a factor of 1.5-fold and produces a device emitted mass median aerodynamic diameter (MMAD) of 1.67 μm. For all ages considered, approximately 70% of the loaded dose reaches the lower lung beyond the lobar bronchi. Moreover, significant and rapid size increase of the aerosol is observed beyond the larynx and illustrates the potential for targeting lower airway deposition. In conclusion, concurrent CFD and realistic in vitro analysis indicates that a combination of multiple new technologies can be implemented to overcome obstacles that currently limit the use of DPIs in children as young as two years of age.

PMID:33716317 | PMC:PMC7945982 | DOI:10.1016/j.jaerosci.2020.105692

J Pediatr Gastroenterol Nutr. 2021 Apr 1;72(4):617-640. doi: 10.1097/MPG.0000000000003046.

ABSTRACT

OBJECTIVES: The aim of the study was to review the evidence regarding the clinical use and value of fecal calprotectin (FC) measurements in different gastrointestinal disorders in children.

METHODS: A literature search was conducted in the PubMed, MEDLINE, EMBASE, and Cochrane databases until October 31, 2019. Subtopics were identified and each assigned to individual authors.

RESULTS: A total of 28 recommendations were voted on using the nominal voting technique. Recommendations are given related to sampling, measurement methods, and results interpretation. The 14 authors anonymously voted on each recommendation using a 9-point scale (1 strongly disagree to 9 fully agree). Consensus was considered achieved if at least 75% of the authors voted 6, 7, 8, or 9.

CONCLUSIONS: Consensus was reached for all recommendations. Limitations for the use of FC in clinical practice include variability in extraction methodology, performance of test kits as well as the need to establish local reference ranges because of the influence of individual factors, such as age, diet, microbiota, and drugs. The main utility of FC measurement at present is in the diagnosis and monitoring of inflammatory bowel disease (IBD) as well as to differentiate it from functional gastrointestinal disorders (FAPDs). FC, however, has neither utility in the diagnosis of infantile colic nor to differentiate between functional and organic constipation. A rise in FC concentration, may alert to the risk of developing necrotizing enterocolitis and help identifying gastrointestinal involvement in children with Henoch-Schönlein purpura. FC measurement is of little value in Cow's Milk Protein Allergy, coeliac disease (CD), and cystic fibrosis. FC does neither help to distinguish bacterial from viral acute gastroenteritis (AGE), nor to diagnose Helicobacter Pylori infection, small intestinal bacterial overgrowth (SIBO), acute appendicitis (AA), or intestinal polyps.

PMID:33716293 | DOI:10.1097/MPG.0000000000003046

J Cyst Fibros. 2021 Mar 11:S1569-1993(21)00046-1. doi: 10.1016/j.jcf.2021.02.011. Online ahead of print.

ABSTRACT

BACKGROUND: Mannitol is a mucoactive hyperosmotic agent used as add-on therapy in patients with cystic fibrosis (CF), administered twice-daily (BID) via a small, portable, breath-actuated dry-powder inhaler. This study was conducted to provide confirmatory evidence of mannitol's efficacy and safety in adults.

METHODS: This multicenter, double-blind, randomized, parallel-group, controlled clinical trial recruited adults (aged ≥18 years) with CF, and forced expiratory volume in 1 second (FEV1) 40-90% predicted. Subjects received either mannitol 400 mg or mannitol 50 mg (control), BID via dry-powder inhaler for 26 weeks. Primary endpoint: FEV1 averaged over the 26-week treatment period.

RESULTS: Of 423 subjects randomized (209 or 214 receiving mannitol 400 mg BID or control, respectively), 373 (88.2%) completed the study, with a similar proportion completing in the two groups. For FEV1 averaged over 26 weeks, mannitol 400 mg BID was statistically superior to control (adjusted mean difference 54 mL [95% CI 8, 100 mL]; p = 0.020). This was supported by sensitivity analyses of the primary endpoint, and by observed improvements in secondary pulmonary function endpoints (eg, absolute adjusted mean difference in percent predicted FEV1 averaged over 26 weeks 1.21% [0.07%, 2.36%]; p = 0.037). Adverse events were mainly mild or moderate in severity, with treatment-related adverse events in 15.5 and 12.2% of subjects receiving mannitol 400 mg BID and control, respectively.

CONCLUSIONS: In adults with CF, mannitol 400 mg BID inhaled as a dry-powder statistically significantly improved lung function (FEV1) compared with control, with this improvement supported by sensitivity analyses and secondary pulmonary function endpoints. Mannitol had a good overall safety and tolerability profile. ClinicalTrials.gov: NCT02134353.

PMID:33715994 | DOI:10.1016/j.jcf.2021.02.011

J Cyst Fibros. 2021 Mar 11:S1569-1993(21)00049-7. doi: 10.1016/j.jcf.2021.02.014. Online ahead of print.

ABSTRACT

BACKGROUND: Home spirometry with regular symptom assessment is one strategy to track lung health to intervene early in episodes of pulmonary exacerbations (PE). In a multi-center randomized controlled trial home spirometry and symptom tracking demonstrated no significant differences regarding the primary clinical endpoint, FEV1, compared to usual care, but did identify differences in healthcare utilization. We used data from the Early Intervention in Cystic Fibrosis Exacerbation (eICE) study to evaluate whether home monitoring of PE is a cost-minimizing intervention in the context of this randomized trial.

METHODS: We reviewed healthcare resource utilization of all 267 eICE participants, including outpatient visits, antibiotics and hospitalizations. Prices were identified in the IBM/Watson MarketScanⓇ Commercial Claims and Encounters Databases and averaged over the 2014-2017 period. Using total healthcare utilization costs, we generated summary statistics by intervention and protocol arm (total cost, mean cost, standard deviation). We performed Welch Two Sample t-tests to determine if total costs and cost by type of utilization differed significantly between groups.

RESULTS: Outpatient visit costs were significantly higher by 13% in the Early Intervention (EI) than in the usual care (UC) arm ($3,345 vs. $2,966). We found no significant differences in outpatient antibiotic, hospitalization, or total health care costs between the arms.

CONCLUSIONS: Within the context of the eICE trial, outpatient visits were significantly higher in those with experimental home spirometry care, but that did not translate into statistically significant differences of overall health care costs between the two arms.

PMID:33715993 | DOI:10.1016/j.jcf.2021.02.014

Endocrinol Diabetes Nutr. 2021 Apr;68(4):215-217. doi: 10.1016/j.endinu.2021.01.003.

NO ABSTRACT

PMID:33715787 | DOI:10.1016/j.endinu.2021.01.003

Biomed Pharmacother. 2021 Mar 11;138:111454. doi: 10.1016/j.biopha.2021.111454. Online ahead of print.

ABSTRACT

Metformin is an oral antihyperglycemic drug widely used to treat type 2 diabetes mellitus (T2DM), acting via indirect activation of 5' Adenosine monophosphate-activated Protein Kinase (AMPK). Beyond the anti-diabetic effect, accumulative pieces of evidence have revealed that metformin also everts a beneficial effect in diverse kidney diseases. In various acute kidney diseases (AKI) animal models, metformin protects renal tubular cells from inflammation, apoptosis, reactive oxygen stress (ROS), endoplasmic reticulum (ER) stress, epithelial-mesenchymal transition (EMT) via AMPK activation. In diabetic kidney disease (DKD), metformin also alleviates podocyte loss, mesangial cells apoptosis, and tubular cells senescence through AMPK-mediated signaling pathways. Besides, metformin inhibits cystic fibrosis transmembrane conductance regulator (CFTR)-mediated fluids secretion and the mammalian target of rapamycin (mTOR)-involved cyst formation negatively regulated by AMPK in autosomal dominant polycystic kidney disease (APDKD). Furthermore, metformin also contributes to the alleviation of urolithiasis and renal cell carcinoma (RCC). As the common pathway for chronic kidney disease (CKD) progressing towards end-stage renal disease (ESRD), renal fibrosis is ameliorated by metformin, to a great extent dependent on AMPK activation. However, clinical data are not always consistent with preclinical data, some clinical investigations showed the unmeaningful even detrimental effect of metformin on T2DM patients with kidney diseases. Most importantly, metformin-associated lactic acidosis (MALA) is a vital issue restricting the application of metformin. Thus, we conclude the application of metformin in kidney diseases and uncover the underlying molecular mechanisms in this review.

PMID:33714781 | DOI:10.1016/j.biopha.2021.111454

Life Sci. 2021 Mar 10:119325. doi: 10.1016/j.lfs.2021.119325. Online ahead of print.

ABSTRACT

AIMS: The emergence of antibiotic tolerance was a tricky problem in the treatment of chronic Pseudomonas aeruginosa-infected cystic fibrosis and burn victims. The quorum sensing (QS) inhibitor may serve as a new tactic for the bacterial resistance by inhibiting the biofilm formation and the production of virulence factors. This study explored the potential of luteolin as a QS inhibitor against P. aeruginosa and the molecular mechanism involved.

MAIN METHODS: Crystal violet staining, CLSM observation, and SEM analysis were carried out to assess the effect of luteolin on biofilm formation. The motility assays and the production of virulence factors were determined to evaluate the QS-inhibitory activity of luteolin. Acyl-homoserine lactone, RT-PCR, and molecular docking assays were conducted to explain its anti-QS mechanisms.

KEY FINDINGS: The biofilm formation, the production of virulence factors, and the motility of P. aeruginosa could be efficiently inhibited by luteolin. Luteolin could also attenuate the accumulation of the QS-signaling molecules N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL) and N-butanoyl-L-homoserine lactone (BHL) (P < 0.01) and downregulate the transcription levels of QS genes (lasR, lasI, rhlR, and rhlI) (P < 0.01). Molecular docking analysis indicated that luteolin had a greater docking affinity with LasR regulator protein compared with OdDHL.

SIGNIFICANCE: This study is important as it reports the molecular mechanisms involved in the anti-biofilm formation activity of luteolin against P. aeruginosa. This study also indicated that luteolin could be helpful when used for the treatment of clinical drug-resistant infections of P. aeruginosa.

PMID:33713665 | DOI:10.1016/j.lfs.2021.119325

Mol Genet Genomic Med. 2021 Mar 13:e1656. doi: 10.1002/mgg3.1656. Online ahead of print.

ABSTRACT

BACKGROUND: New drugs that target the basic defect in cystic fibrosis (CF) patients may now be used in a large number of patients carrying responsive mutations. Nevertheless, further research is needed to extend the benefit of these treatments to patients with rare mutations that are still uncharacterized in vitro and that are not included in clinical trials. For this purpose, ex vivo models are necessary to preliminary assessing the effect of CFTR modulators in these cases.

METHOD: We report the clinical effectiveness of lumacaftor/ivacaftor therapy prescribed to a CF child with a rare genetic profile (p.Phe508del/p.Gly970Asp) after testing the drug on nasal epithelial cells. We observed a significant drop of the sweat chloride value, as of the lung clearance index. A longer follow-up period is needed to define the effects of therapy on pancreatic status, although an increase of the fecal elastase values was found.

CONCLUSION: Drug response obtained on nasal epithelial cells correlates with changes in vivo therapeutic endpoints and can be a predictor of clinical efficacy of novel drugs especially in pediatric patients.

PMID:33713579 | DOI:10.1002/mgg3.1656

Immunol Rev. 2021 Mar 12. doi: 10.1111/imr.12959. Online ahead of print.

ABSTRACT

Immunity against different Mycobacteria species targeting the lung requires distinctly different pulmonary immune responses for bacterial clearance. Many parameters of acquired and regulatory immune responses differ quantitatively and qualitatively from immunity during infection with Mycobacteria species. Nontuberculosis Mycobacteria species (NTM) Mycobacterium avium- (M avium), Mycobacterium abscessus-(M abscessus), and the Mycobacteria species Mycobacterium tuberculosis-(Mtb). Herein, we discuss the potential implications of acquired and regulatory immune responses in the context of animal and human studies, as well as future directions for efforts to treat Mycobacteria diseases.

PMID:33713043 | DOI:10.1111/imr.12959