Adrenomedullin Improves Fertility and Promotes Pinopodes and Cell Junctions in the Peri-Implantation Endometrium.

Biol Reprod. 2017 Aug 28;:

Authors: Matson BC, Pierce SL, Espenschied ST, Holle E, Sweatt IH, Davis ES, Tarran R, Young SL, Kohout TA, van Duin M, Caron KM

Abstract
Implantation is a complex event demanding contributions from both embryo and endometrium. Despite advances in assisted reproduction, endometrial receptivity defects persist as a barrier to successful implantation in women with infertility. We previously demonstrated that maternal haploinsufficiency for the endocrine peptide adrenomedullin (AM) in mice confers a sub-fertility phenotype characterized by defective uterine receptivity and sparse epithelial pinopode coverage. The strong link between AM and implantation suggested the compelling hypothesis that administration of AM prior to implantation may improve fertility, protect against complications, and ultimately lead to better maternal and fetal outcomes. Here, we demonstrate that intrauterine delivery of AM prior to blastocyst transfer improves the embryo implantation rate and spacing within the uterus. We then use genetic decrease-of-function and pharmacologic gain-of-function mouse models to identify potential mechanisms by which AM confers enhanced implantation success. In epithelium, we find that AM accelerates the kinetics of pinopode formation and water transport, and in stroma, that AM promotes connexin 43 expression, gap junction communication, and barrier integrity of the primary decidual zone. Ultimately, our findings advance our understanding of the contributions of AM to uterine receptivity and suggest potential broad use for AM as therapy to encourage healthy embryo implantation, for example in combination with in vitro fertilization.

PMID: 29025060 [PubMed - as supplied by publisher]

Formulation and delivery strategies of ibuprofen: Challenges and opportunities.

Drug Dev Ind Pharm. 2017 Oct 12;:1-28

Authors: Irvine J, Afrose A, Islam N

Abstract
Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID) is mostly administered orally and topically to relieve acute pain and fever. Due to its mode of action this drug may be useful in the treatment regimens of other, more chronic conditions, like cystic fibrosis. This drug is poorly soluble in aqueous media and thus the rate of dissolution from the currently available solid dosage forms is limited. This leads to poor bioavailability at high doses after oral administration, thereby increasing the risk of unwanted adverse effects. The poor solubility is a problem for developing injectable solution dosage forms. Because of its poor skin permeability, it is difficult to obtain an effective therapeutic concentration from topical preparations. This review aims to give a brief insight into the status of ibuprofen dosage forms and their limitations, particle/crystallization technologies for improving formulation strategies as well as suggesting its incorporation into the pulmonary drug delivery systems for achieving better therapeutic action at low dose.

PMID: 29022772 [PubMed - as supplied by publisher]

Gene Disruption in Scedosporium aurantiacum: Proof of Concept with the Disruption of SODC Gene Encoding a Cytosolic Cu,Zn-Superoxide Dismutase.

Mycopathologia. 2017 Oct 11;:

Authors: Pateau V, Razafimandimby B, Vandeputte P, Thornton CR, Guillemette T, Bouchara JP, Giraud S

Abstract
Scedosporium species are opportunistic pathogens responsible for a large variety of infections in humans. An increasing occurrence was observed in patients with underlying conditions such as immunosuppression or cystic fibrosis. Indeed, the genus Scedosporium ranks the second among the filamentous fungi colonizing the respiratory tracts of the CF patients. To date, there is very scarce information on the pathogenic mechanisms, at least in part because of the limited genetic tools available. In the present study, we successfully developed an efficient transformation and targeted gene disruption approach on the species Scedosporium aurantiacum. The disruption cassette was constructed using double-joint PCR procedure, and resistance to hygromycin B as the selection marker. This proof of concept was performed on the functional gene SODC encoding the Cu,Zn-superoxide dismutase. Disruption of the SODC gene improved susceptibility of the fungus to oxidative stress. This technical advance should open new research areas and help to better understand the biology of Scedosporium species.

PMID: 29022198 [PubMed - as supplied by publisher]

Anti-fibrotic effects of valproic acid: role of HDAC inhibition and associated mechanisms.

Epigenomics. 2016 Aug;8(8):1087-101

Authors: Khan S, Ahirwar K, Jena G

Abstract
Tissue injuries and pathological insults produce oxidative stress, genetic and epigenetic alterations, which lead to an imbalance between pro- and anti-fibrotic molecules, and subsequent accumulation of extracellular matrix, thereby fibrosis. Various molecular pathways play a critical role in fibroblasts activation, which promotes the extracellular matrix production and accumulation. Recent reports highlighted that histone deacetylases (HDACs) are upregulated in various fibrotic disorders and play a central role in fibrosis, while HDAC inhibitors exert antifibrotic effects. Valproic acid is a first-line anti-epileptic drug and a proven HDAC inhibitor. This review provides the current research and novel insights on antifibrotic effects of valproic acid in various fibrotic conditions with an emphasis on the possible strategies for treatment of fibrosis.

PMID: 27411759 [PubMed - indexed for MEDLINE]

Neutrophils from Patients with Primary Ciliary Dyskinesia Display Reduced Chemotaxis to CXCR2 Ligands.

Front Immunol. 2017;8:1126

Authors: Cockx M, Gouwy M, Godding V, De Boeck K, Van Damme J, Boon M, Struyf S

Abstract
Primary ciliary dyskinesia (PCD), cystic fibrosis (CF), and chronic obstructive airway disease are characterized by neutrophilic inflammation in the lungs. In CF and chronic obstructive airway disease, improper functioning of neutrophils has been demonstrated. We hypothesized that the pulmonary damage in PCD might be aggravated by abnormal functioning neutrophils either as a primary consequence of the PCD mutation or secondary to chronic inflammation. We analyzed chemotactic responses and chemoattractant receptor expression profiles of peripheral blood neutrophils from 36 patients with PCD, 21 healthy children and 19 healthy adults. We stimulated peripheral blood monocytes from patients and healthy controls and measured CXCL8 and IL-1β production with ELISA. PCD neutrophils displayed reduced migration toward CXCR2 ligands (CXCL5 and CXCL8) in the shape change, microchamber and microslide chemotaxis assays, whereas leukotriene B4 and complement component 5a chemotactic responses were not significantly different. The reduced response to CXCL8 was observed in all subgroups of patients with PCD (displaying either normal ultrastructure, dynein abnormalities or central pair deficiencies) and correlated with lung function. CXCR2 was downregulated in about 65% of the PCD patients, suggestive for additional mechanisms causing CXCR2 impairment. After treatment with the TLR ligands lipopolysaccharide and peptidoglycan, PCD monocytes produced more CXCL8 and IL-1β compared to controls. Moreover, PCD monocytes also responded stronger to IL-1β stimulation in terms of CXCL8 production. In conclusion, we revealed a potential link between CXCR2 and its ligand CXCL8 and the pathogenesis of PCD.

PMID: 29018439 [PubMed]

Syk inhibitor R406 down-regulates inflammation in an in vitro model of Pseudomonas aeruginosa infection.

Can J Physiol Pharmacol. 2017 Oct 11;:

Authors: Alhazmi A, Choi J, Ulanova M

Abstract
As Pseudomonas aeruginosa infections are characterized by strong inflammation of infected tissues anti-inflammatory therapies in combination with antibiotics have been considered for the treatment of associated diseases. Syk tyrosine kinase is an important regulator of inflammatory responses, and its specific inhibition was explored as a therapeutic option in several inflammatory conditions; however, this has not been studied in bacterial infections. We used a model of in vitro infection of human monocytic cell line THP-1 and lung epithelial cell line H292 with both wild type and flagella-deficient mutant of P. aeruginosa strain K, as well as with clinical isolates from cystic fibrosis patients, to study the effect of a small molecule Syk inhibitor R406 on inflammatory responses induced by this pathogen. One-hour long pretreatment of THP-1 cells with 10 μM R406 resulted in a significant down-regulation of the expression of the adhesion molecule ICAM-1, pro-inflammatory cytokines TNFα and IL-1β, and phosphorylated signaling proteins ERK2, JNK, p-38, and IκBα, as well as significantly decreased TNF-α release by infected H292 cells. The results suggest that Syk is involved in the regulation of inflammatory responses to P. aeruginosa, and R406 may potentially be useful in dampening the damage caused by severe inflammation associated with this infection.

PMID: 29020462 [PubMed - as supplied by publisher]

The FDA's Experience with Ivacaftor in Cystic Fibrosis: Establishing Efficacy Using In Vitro Data in Lieu of a Clinical Trial.

Ann Am Thorac Soc. 2017 Oct 11;:

Authors: Durmowicz AG, Lim R, Rogers H, Rosebraugh CJ, Chowdhury BA

PMID: 29020455 [PubMed - as supplied by publisher]

Identification of a targeted and testable antiarrhythmic therapy for long-QT syndrome type 2 using a patient-specific cellular model.

Eur Heart J. 2017 Jul 21;:

Authors: Mehta A, Ramachandra CJA, Singh P, Chitre A, Lua CH, Mura M, Crotti L, Wong P, Schwartz PJ, Gnecchi M, Shim W

Abstract
Aims: Loss-of-function mutations in the hERG gene causes long-QT syndrome type 2 (LQT2), a condition associated with reduced IKr current. Four different mutation classes define the molecular mechanisms impairing hERG. Among them, Class 2 mutations determine hERG trafficking defects. Lumacaftor (LUM) is a drug acting on channel trafficking already successfully tested for cystic fibrosis and its safety profile is well known. We hypothesize that LUM might rescue also hERG trafficking defects in LQT2 and exert anti-arrhythmic effects.
Methods and results: From five LQT2 patients, we generated lines of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) harbouring Class 1 and 2 mutations. The effects of LUM on corrected field potential durations (cFPD) and calcium-handling irregularities were verified by multi electrode array and by calcium transients imaging, respectively. Molecular analysis was performed to clarify the mechanism of action of LUM on hERG trafficking and calcium handling. Long-QT syndrome type 2 induced pluripotent stem cell-derived cardiomyocytes mimicked the clinical phenotypes and showed both prolonged cFPD (grossly equivalent to the QT interval) and increased arrhythmias. Lumacaftor significantly shortened cFPD in Class 2 iPSC-CMs by correcting the hERG trafficking defect. Furthermore, LUM seemed to act also on calcium handling by reducing RyR2S2808 phosphorylation in both Class 1 and 2 iPSC-CMs.
Conclusion: Lumacaftor, a drug already in clinical use, can rescue the pathological phenotype of LQT2 iPSC-CMs, particularly those derived from Class 2 mutated patients. Our results suggest that the use of LUM in LQT2 patients not protected by β-blockers is feasible and may represent a novel therapeutic option.

PMID: 29020304 [PubMed - as supplied by publisher]

Glutaminolysis Promotes Collagen Translation and Stability via α-ketoglutarate Mediated mTOR Activation and Proline Hydroxylation.

Am J Respir Cell Mol Biol. 2017 Oct 11;:

Authors: Ge J, Cui H, Xie N, Banerjee S, Guo S, Dubey S, Barnes S, Liu G

Abstract
Glutaminolysis is the metabolic process of glutamine, of which aberration has been implicated in several pathogeneses. While we and others recently found a diversity of metabolic dysregulations in organ fibrosis, it is unknown if glutaminolysis regulates the pro-fibrotic activities of myofibroblasts, the primary effector in this pathology. In this study, we found that lung myofibroblasts demonstrated significantly augmented glutaminolysis that was mediated by elevated Glutaminase 1 (Gls1). Inhibition of glutaminolysis by specific Gls1 inhibitors CB-839 and BPTES as well as Gls1 siRNA blunted the expression of collagens, but not that of Fibronectin, Elastin or myofibroblastic marker smooth muscle actin α (SMA-α). We found that glutaminolysis enhanced collagen translation and stability, which were mediated by glutaminolysis dependent mammalian target of rapamycin complex 1 (mTORC1) activation and collagen proline hydroxylation, respectively. Furthermore, we found that level of glutaminolytic end product, α-ketoglutarate (α-KG), was increased in myofibroblasts. Similar to glutaminolysis, α-KG activated mTORC1 and promoted expression of collagens, but not that of Fibronectin, Elastin, or SMA-α. α-KG also remarkably inhibited collagen degradation in fibroblasts. Taken together, our studies identified a previously unrecognized mechanism by which a major metabolic program regulates the exuberant production of collagens in myofibroblasts and suggest glutaminolysis being a novel therapeutic target for treating organ fibrosis, including idiopathic pulmonary fibrosis (IPF).

PMID: 29019707 [PubMed - as supplied by publisher]

Activity of Bacteriophages in Removing Biofilms of Pseudomonas aeruginosa Isolates from Chronic Rhinosinusitis Patients.

Front Cell Infect Microbiol. 2017;7:418

Authors: Fong SA, Drilling A, Morales S, Cornet ME, Woodworth BA, Fokkens WJ, Psaltis AJ, Vreugde S, Wormald PJ

Abstract
Introduction:Pseudomonas aeruginosa infections are prevalent amongst chronic rhinosinusitis (CRS) sufferers. Many P. aeruginosa strains form biofilms, leading to treatment failure. Lytic bacteriophages (phages) are viruses that infect, replicate within, and lyse bacteria, causing bacterial death. Aim: To assess the activity of a phage cocktail in eradicating biofilms of ex vivo P.aeruginosa isolates from CRS patients. Methods: P. aeruginosa isolates from CRS patients with and without cystic fibrosis (CF) across three continents were multi-locus sequence typed and tested for antibiotic resistance. Biofilms grown in vitro were treated with a cocktail of four phages (CT-PA). Biofilm biomass was measured after 24 and 48 h, using a crystal violet assay. Phage titrations were performed to confirm replication of the phages. A linear mixed effects model was applied to assess the effects of treatment, time, CF status, and multidrug resistance on the biomass of the biofilm. Results: The isolates included 44 strain types. CT-PA treatment significantly reduced biofilm biomass at both 24 and 48 h post-treatment (p < 0.0001), regardless of CF status or antibiotic resistance. Biomass was decreased by a median of 76% at 48 h. Decrease in biofilm was accompanied by a rise in phage titres for all except one strain. Conclusion: A single dose of phages is able to significantly reduce biofilms formed in vitro by a range of P.aeruginosa isolates from CRS patients. This represents an exciting potential and novel targeted treatment for P. aeruginosa biofilm infections and multidrug resistant bacteria.

PMID: 29018773 [PubMed - in process]

The calcineurin-NFAT axis contributes to host defense during Pseudomonas aeruginosa lung infection.

J Leukoc Biol. 2017 Oct 10;:

Authors: Pang Z, Junkins RD, MacNeil AJ, McCormick C, Cheng Z, Chen WM, Lin TJ

Abstract
Infection with the opportunistic pathogen Pseudomonas aeruginosa is effectively controlled through tightly coordinated inflammation in healthy individuals. Dysregulated inflammation in cystic fibrosis greatly increases susceptibility to P. aeruginosa and lung damage. Recently, we identified regulator of calcineurin-1, a small, conserved protein that suppresses the NFAT pathway by inhibition of calcineurin and functions as a central negative regulator of multiple inflammatory transcription factors after P. aeruginosa lung infection, implying a role for the canonical NFAT pathway in P. aeruginosa infection. Calcineurin is a calcium-calmodulin-responsive phosphatase that dephosphorylates NFAT and promotes NFAT nuclear translocation and transcriptional activity. The contribution of the NFAT pathway to host defense against P. aeruginosa remains poorly characterized. In this study, we found that NFAT was rapidly and transiently activated after P. aeruginosa infection both in vitro and in vivo. Deficiency of calcineurin Aβ caused impaired activation of NFAT and decreased inflammatory cytokine production in vivo. Finally, we demonstrated that the cross-talk between the NFAT and NFкB pathways coordinately transactivate host response genes during P. aeruginosa infection. Together, these results demonstrate for the first time that NFAT is activated through calcineurin and interacts with NFкB after P. aeruginosa lung infection, and contributes to the host inflammatory response.

PMID: 29018150 [PubMed - as supplied by publisher]

A 17-Year Nationwide Study of Burkholderia cepacia Complex Bloodstream Infections Among Patients in the United States Veterans Health Administration.

Clin Infect Dis. 2017 Oct 15;65(8):1253-1259

Authors: El Chakhtoura NG, Saade E, Wilson BM, Perez F, Papp-Wallace KM, Bonomo RA

Abstract
Background: Burkholderia cepacia complex (Bcc) are a group of multidrug-resistant gram-negative bacteria rarely reported in patients without cystic fibrosis (CF) or immunocompromising conditions. We investigated Bcc bloodstream infections (BSIs) in a cohort of non-CF patients from the US Veterans Health Administration (VHA).
Methods: Using VHA databases, we identified patients with Bcc BSI at facilities nationwide from 1999 through 2015. We ascertained clinical characteristics, treatments, and outcomes and identified factors associated with 30-day mortality in logistic regression analysis.
Results: We identified 248 patients with Bcc BSI, who were of advanced age (mean, 68 years), chronically ill, and had severe disease. The most common sources were central venous catheters (41%) and pneumonia (20%). Most cases were hospital-acquired (155 [62%]) or healthcare-associated (70 [28%]). Mortality at 14, 30, and 90 days was 16%, 25%, and 36%, respectively. Trimethoprim-sulfamethoxazole (TMP-SMX) and fluoroquinolones were active against 94% and 88% of isolates, respectively. Susceptibility to ceftazidime and meropenem occurred in approximately 70% of the isolates. The most prescribed antibiotics were fluoroquinolones (35%), followed by carbapenems (20%), TMP-SMX (18.5%), and ceftazidime (11%). In regression analysis, age (OR, 1.06 [95% confidence interval {CI}, 1.02-1.10], per added year) and the Pitt bacteremia score (OR, 1.65 [95% CI, 1.44-1.94], per unit increase) were associated with higher 30-day mortality.
Conclusions: In this large cohort of BSIs caused by Bcc, cases were mostly hospital-acquired and we observed high mortality, significant resistance to ceftazidime, and limited use of TMP-SMX. These observations add to our understanding of Bcc infection in non-CF patients and highlight the need for interventions to improve their outcome.

PMID: 29017247 [PubMed - in process]

Short-length ligamentum arteriosum as a cause of congenital narrowing of the left main stem bronchus.

Pediatr Pulmonol. 2016 Dec;51(12):1356-1361

Authors: Sacco O, Santoro F, Ribera E, Magnano GM, Rossi GA

Abstract
An entity that has received little attention as cause or recurrent respiratory disorder is the narrowing of the left main stem bronchus. When not associated with congenital heart disorders, this condition has been ascribed to primary localized malacia of the bronchial cartilages or to the anterior displacement of the descending aorta in front to the adjacent vertebral bodies. Four girls were evaluated for recurrent/chronic respiratory symptoms. A pulsatile extrinsic compression on the posterior bronchial wall of the left main stem bronchus was detected, pressed between the descending aorta, posteriorly, and the left pulmonary artery, anteriorly. The two arteries were closely linked together by a short-length ligamentum that was resected, allowing the mobilization of the aorta with posterior aortopexy, stabilizing the space created between the pulmonary artery and the descending aorta. The reduced compression on the left main bronchus resulted in the enlargement of its caliber and in a marked improvement of the respiratory symptoms. Pediatr Pulmonol. 2016;51:1356-1361. © 2016 Wiley Periodicals, Inc.

PMID: 27128381 [PubMed - indexed for MEDLINE]

17 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2017/10/11

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

17 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2017/10/11

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Pancreatitis and pancreatic cystosis in Cystic Fibrosis.

J Cyst Fibros. 2017 Sep 19;:

Authors: Freeman AJ, Ooi CY

Abstract
The pathologic effects of an altered cystic fibrosis transmembrane receptor (CFTR) protein on the exocrine pancreas is ubiquitous and of varying severity. In this section, pancreatitis and pancreatic cystosis are covered.

PMID: 28986028 [PubMed - as supplied by publisher]

Cystic Fibrosis-related cirrhosis.

J Cyst Fibros. 2017 Sep 16;:

Authors: Leung DH, Narkewicz MR

Abstract
While liver involvement is common in cystic fibrosis, the major liver disorder with impact on the clinical outcome of individuals with CF is the development of multilobular cirrhosis with progression to portal hypertension. Interestingly, this is a disorder primarily of children and adolescents. We review the proposed pathogenesis, clinical presentation, diagnostic work-up, medical and surgical management, and complications of CF cirrhosis.

PMID: 28986027 [PubMed - as supplied by publisher]

Nutrition: Prevention and management of nutritional failure in Cystic Fibrosis.

J Cyst Fibros. 2017 Sep 16;:

Authors: Sullivan JS, Mascarenhas MR

Abstract
Close monitoring of nutritional status is critical to the overall health of a patient with CF. As part of routine CF care, measurement of weight and height (and calculation of weight/length or BMI as appropriate) should be performed and analyzed at each visit. Early recognition of nutritional risk is imperative and evaluation with a multidisciplinary team should be performed to assess for caloric intake, caloric malabsorption, and other causes of poor weight gain and growth. Many tools are available to use for intervention, including oral supplementation, behavioral interventions, medications, nutritional therapies, and enteral tube feeding.

PMID: 28986026 [PubMed - as supplied by publisher]

Introduction.

J Cyst Fibros. 2017 Sep 18;:

Authors: Freedman SD, Wilschanski M

PMID: 28986025 [PubMed - as supplied by publisher]

Cystic Fibrosis and gastroesophageal reflux disease.

J Cyst Fibros. 2017 Sep 25;:

Authors: Maqbool A, Pauwels A

Abstract
Gastroesophageal reflux is common in children and adults with cystic fibrosis (CF). Pathological gastroesophageal reflux disease (GERD) is also frequent in patients of all ages with CF. This article reviews the pathophysiology, diagnostic work-up, management options, complications, and future directions in the evaluation and management of GERD - unique to and pertinent for - patients with CF in particular.

PMID: 28986024 [PubMed - as supplied by publisher]