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Article ; Online: Fecal dysbiosis and inflammation in intestinal-specific Cftr knockout mice on regimens preventing intestinal obstruction.

Young, Sarah M / Woode, Rowena A / Williams, Estela C / Ericsson, Aaron C / Clarke, Lane L

2023 Volume 56, Issue 3, Page(s) 247–264

Abstract: Chronic intestinal inflammation is a poorly understood manifestation of cystic fibrosis (CF), which may be refractory to ion channel CF transmembrane conductance regulator (CFTR) modulator therapy. People with CF exhibit intestinal dysbiosis, which has ... ...

Abstract	Chronic intestinal inflammation is a poorly understood manifestation of cystic fibrosis (CF), which may be refractory to ion channel CF transmembrane conductance regulator (CFTR) modulator therapy. People with CF exhibit intestinal dysbiosis, which has the potential for stimulating intestinal and systemic inflammation. CFTR is expressed in organ epithelia, leukocytes, and other tissues. Here, we investigate the contribution of intestinal epithelium-specific loss of Cftr [iCftr knockout (KO)] to dysbiosis and inflammation in mice treated with either of two antiobstructive dietary regimens necessary to maintain CF mouse models [polyethylene glycol (PEG) laxative or a liquid diet (LiqD)]. Feces collected from iCftr KO mice and their wild-type (WT) sex-matched littermates were used to measure fecal calprotectin to evaluate inflammation and to perform 16S rRNA sequencing to characterize the gut microbiome. Fecal calprotectin was elevated in iCftr KO relative to WT mice that consumed either PEG or LiqD. PEG iCftr KO mice did not show a change in α diversity versus WT mice but demonstrated a significant difference in microbial composition (β diversity) with included increases in the phylum Proteobacteria, the family
MeSH term(s)	Animals ; Humans ; Mice ; Clostridioides difficile/genetics ; Cystic Fibrosis/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Dysbiosis/microbiology ; Expectorants/therapeutic use ; Feces ; Inflammation ; Intestinal Obstruction ; Leukocyte L1 Antigen Complex/therapeutic use ; Mice, Inbred CFTR ; Mice, Knockout ; RNA, Ribosomal, 16S
Chemical Substances	Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6) ; Expectorants ; Leukocyte L1 Antigen Complex ; RNA, Ribosomal, 16S ; Cftr protein, mouse
Language	English
Publishing date	2023-12-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	2038823-8
ISSN	1531-2267 ; 1094-8341
ISSN (online)	1531-2267
ISSN	1094-8341
DOI	10.1152/physiolgenomics.00077.2023
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Article: Fecal Dysbiosis and Inflammation in Intestinal-Specific Cftr Knockout Mice on Regimens Preventing Intestinal Obstruction.

Young, Sarah M / Woode, Rowena A / Williams, Estela / Ericsson, Aaron / Clarke, Lane L

bioRxiv : the preprint server for biology

2023

Abstract: Chronic intestinal inflammation is a poorly understood manifestation of Cystic Fibrosis (CF), which may be refractory to ion channel CFTR modulator therapy. People with CF exhibit intestinal dysbiosis which has potential for stimulating intestinal and ... ...

Abstract	Chronic intestinal inflammation is a poorly understood manifestation of Cystic Fibrosis (CF), which may be refractory to ion channel CFTR modulator therapy. People with CF exhibit intestinal dysbiosis which has potential for stimulating intestinal and systemic inflammation. CFTR is expressed in organ epithelia and in the leukocyte population. Here, we investigate the contribution of intestinal epithelial-specific loss of Cftr (iCftr KO) to dysbiosis and inflammation in mice treated with either of two anti-obstructive dietary regimens necessary to maintain CF mouse models (PEG laxative or a liquid diet, LiqD). Feces collected from iCftr KO mice and their wildtype (WT) sex-matched littermates were used to measure fecal calprotectin and to perform 16S rRNA sequencing to characterize the gut microbiome. Fecal calprotectin was elevated in iCftr KO relative to WT samples of mice consuming either PEG or LiqD. PEG iCftr KO mice did not show a change in α-diversity versus WT but demonstrated a significant difference in microbial composition (β-diversity) with increases in phylum New and noteworthy: Chronic intestinal inflammation is a manifestation of cystic fibrosis (CF), a disease caused by loss of the anion channel CFTR that is expressed in many tissues. This study shows that intestinal epithelial cell-specific loss of CFTR (iCftr KO) in mice is sufficient to induce intestinal dysbiosis and inflammation. Studies were performed on mice consuming either dietary regimen (PEG laxative or liquid diet) routinely used to prevent obstruction in CF mice.
Language	English
Publishing date	2023-07-26
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.07.24.550378
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Book ; Thesis: Regulation of ion transport across equine colon

Clarke, Lane L.

1989

Author's details	by Lane L. Clarke
Keywords	Intestinal Absorption ; Sodium / pharmacokinetics ; Chlorides / pharmacokinetics ; Colon / physiology ; Horses
Size	VI, 167 S. : Ill., graph. Darst.
Publishing country	United States
Document type	Book ; Thesis
Thesis / German Habilitation thesis	North Carolina State Univ., Diss., 1989
Note	Kopie, erschienen im Verl. Univ. Microfilms Internat., Ann Arbor, Mich., 1992
HBZ-ID	HT004242476
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Article ; Online: Goblet cell hyperplasia is not epithelial-autonomous in the Cftr knockout intestine.

Walker, Nancy M / Liu, Jinghua / Young, Sarah M / Woode, Rowena A / Clarke, Lane L

American journal of physiology. Gastrointestinal and liver physiology

2021 Volume 322, Issue 2, Page(s) G282–G293

Abstract: Goblet cell hyperplasia is an important manifestation of cystic fibrosis (CF) disease in epithelial-lined organs. Explants of CF airway epithelium show normalization of goblet cell numbers; therefore, we hypothesized that small intestinal enteroids from ... ...

Abstract	Goblet cell hyperplasia is an important manifestation of cystic fibrosis (CF) disease in epithelial-lined organs. Explants of CF airway epithelium show normalization of goblet cell numbers; therefore, we hypothesized that small intestinal enteroids from Cftr knockout (KO) mice would not exhibit goblet cell hyperplasia. Toll-like receptors 2 and 4 (Tlr2 and Tlr4) were investigated as markers of inflammation and influence on goblet cell differentiation. Ex vivo studies found goblet cell hyperplasia in Cftr KO jejunum compared with wild-type (WT) mice. IL-13, SAM pointed domain-containing ETS transcription factor (Spdef), Tlr2, and Tlr4 protein expression were increased in Cftr KO intestine relative to WT. In contrast, WT and Cftr KO enteroids did not exhibit differences in basal or IL-13-stimulated goblet cell numbers, or differences in expression of Tlr2, Tlr4, and Spdef. Ileal goblet cell numbers in Cftr KO/Tlr4 KO and Cftr KO/Tlr2 KO mice were not different from Cftr KO mice, but enumeration was confounded by altered mucosal morphology. Treatment with Tlr4 agonist LPS did not affect goblet cell numbers in WT or Cftr KO enteroids, whereas the Tlr2 agonist Pam3Csk4 stimulated goblet cell hyperplasia in both genotypes. Pam3Csk4 stimulation of goblet cell numbers was associated with suppression of Notch1 and Neurog3 expression and upregulated determinants of goblet cell differentiation. We conclude that goblet cell hyperplasia and inflammation of the Cftr KO small intestine are not exhibited by enteroids, indicating that this manifestation of CF intestinal disease is not epithelial-automatous but secondary to the altered CF intestinal environment.
MeSH term(s)	Animals ; Cystic Fibrosis/genetics ; Cystic Fibrosis/metabolism ; Goblet Cells/metabolism ; Hyperplasia/metabolism ; Inflammation/metabolism ; Intestines/metabolism ; Mice, Knockout ; Organoids/metabolism ; Signal Transduction/physiology ; Mice
Language	English
Publishing date	2021-12-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	603840-2
ISSN	1522-1547 ; 0193-1857
ISSN (online)	1522-1547
ISSN	0193-1857
DOI	10.1152/ajpgi.00290.2021
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Article ; Online: Efficacy of an isoxazole-3-carboxamide analog of pleconaril in mouse models of Enterovirus-D68 and Coxsackie B5.

Antiviral research

2023 Volume 216, Page(s) 105654

Abstract: Enteroviruses (EV) cause a number of life-threatening infectious diseases. EV-D68 is known to cause respiratory illness in children that can lead to acute flaccid myelitis. Coxsackievirus B5 (CVB5) is commonly associated with hand-foot-mouth disease. ... ...

Abstract	Enteroviruses (EV) cause a number of life-threatening infectious diseases. EV-D68 is known to cause respiratory illness in children that can lead to acute flaccid myelitis. Coxsackievirus B5 (CVB5) is commonly associated with hand-foot-mouth disease. There is no antiviral treatment available for either. We have developed an isoxazole-3-carboxamide analog of pleconaril (11526092) which displayed potent inhibition of EV-D68 (IC
MeSH term(s)	Animals ; Mice ; Enterovirus D, Human ; Isoxazoles/pharmacology ; Isoxazoles/therapeutic use ; Cryoelectron Microscopy ; Enterovirus Infections/drug therapy ; Enterovirus ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Hand, Foot and Mouth Disease/drug therapy ; Enterovirus B, Human
Chemical Substances	pleconaril (9H4570Q89D) ; Isoxazoles ; Antiviral Agents
Language	English
Publishing date	2023-06-14
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2023.105654
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Article ; Online: Clinicians' views and experiences of prescribing oral anticoagulants for stroke prevention in atrial fibrillation: A qualitative meta-synthesis.

Pritchett, Ruth V / Clarke, Joanne L / Jolly, Kate / Clarkesmith, Danielle / Bem, Danai / Turner, Grace M / Thomas, G Neil / Lane, Deirdre A

PloS one

2020 Volume 15, Issue 5, Page(s) e0232484

Abstract: Background: Globally, over 33 million people have atrial fibrillation (AF). In eligible patients, oral anticoagulation (OAC) is recommended for stroke risk reduction. Despite recent increases in OAC prescribing, global under-prescription to high-risk AF ...

Abstract	Background: Globally, over 33 million people have atrial fibrillation (AF). In eligible patients, oral anticoagulation (OAC) is recommended for stroke risk reduction. Despite recent increases in OAC prescribing, global under-prescription to high-risk AF patients and inappropriate prescription to low-risk patients is leading to unnecessary risk of stroke and haemorrhage. This meta-synthesis explored clinicians' beliefs and experiences regarding OAC prescription to AF patients, highlighting barriers to stroke prevention and informing future clinician-focused interventions. Methods and results: A qualitative meta-synthesis exploring clinicians' views and experiences of prescribing OACs for stroke prevention in AF patients. Databases including MEDLINE, EMBASE, PsychINFO and CINAHL were searched to June 2018, with a further Medline search to February 2020. Thematic synthesis was performed with data coding, descriptive theme categorisation and generation of analytical themes. From 3499 records, 101 full text papers were screened, with 13 eligible studies identified. Four analytical themes were found to affect clinicians' prescribing: (i) 'Clinicians' intellectual and emotional responses to the evidence'; (ii) 'Prescribing in primary and secondary care'; (iii) 'Clinicians' views of how patients' characteristics and opinions influence prescribing'; and (iv) 'Clinicians' views on their interactions with patients'. Conclusions: This review highlights focal points for future clinician-focused interventions to improve guideline-adherent OAC prescription in AF patients. Interventions should aim to improve clinicians' knowledge around NOAC prescription and stroke and haemorrhage risk assessment tools as well as their emotional responses to difficult prescribing scenarios. Multidisciplinary interventions promoting cohesive care and input from different clinicians to overcome time-related barriers may increase guideline-adherent OAC prescription for AF patients.
MeSH term(s)	Administration, Oral ; Anticoagulants/administration & dosage ; Anticoagulants/adverse effects ; Anticoagulants/therapeutic use ; Atrial Fibrillation/complications ; Atrial Fibrillation/drug therapy ; Attitude of Health Personnel ; Hemorrhage/etiology ; Hemorrhage/prevention & control ; Humans ; Inappropriate Prescribing ; Physician-Patient Relations ; Practice Guidelines as Topic ; Practice Patterns, Physicians' ; Risk Factors ; Stroke/etiology ; Stroke/prevention & control
Chemical Substances	Anticoagulants
Language	English
Publishing date	2020-05-07
Publishing country	United States
Document type	Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't ; Systematic Review
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0232484
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Article ; Online: Prebiotic and probiotic supplementation and the tryptophan-kynurenine pathway: A systematic review and meta analysis.

Purton, Terry / Staskova, Lada / Lane, Melissa M / Dawson, Samantha L / West, Madeline / Firth, Joseph / Clarke, Gerard / Cryan, John F / Berk, Michael / O'Neil, Adrienne / Dean, Olivia / Hadi, Amir / Honan, Cynthia / Marx, Wolfgang

Neuroscience and biobehavioral reviews

2021 Volume 123, Page(s) 1–13

Abstract: This systematic review aimed to synthesise the results from studies investigating the effects of prebiotics and probiotics on kynurenine pathway metabolism. Thirteen studies were identified for inclusion, comprising 12 probiotic and two prebiotic arms. ... ...

Abstract	This systematic review aimed to synthesise the results from studies investigating the effects of prebiotics and probiotics on kynurenine pathway metabolism. Thirteen studies were identified for inclusion, comprising 12 probiotic and two prebiotic arms. Participants included healthy individuals and individuals with various clinical conditions. Twelve metabolites were examined across the studies, using a range of biological samples. Across all interventions, 11 reported an effect on ≤ metabolite. Although limited by clinical and methodological heterogeneity, pooled analysis (n = 253) found probiotics to significantly affect serum kynurenine (g = 0.315, CI = 0.070 to 0.560, p = 0.012, 4 studies, I
MeSH term(s)	Humans ; Kynurenine ; Prebiotics ; Probiotics ; Tryptophan
Chemical Substances	Prebiotics ; Kynurenine (343-65-7) ; Tryptophan (8DUH1N11BX)
Language	English
Publishing date	2021-01-19
Publishing country	United States
Document type	Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't ; Review ; Systematic Review
ZDB-ID	282464-4
ISSN	1873-7528 ; 0149-7634
ISSN (online)	1873-7528
ISSN	0149-7634
DOI	10.1016/j.neubiorev.2020.12.026
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Article: A guide to Ussing chamber studies of mouse intestine.

Clarke, Lane L

American journal of physiology. Gastrointestinal and liver physiology

2009 Volume 296, Issue 6, Page(s) G1151–66

Abstract: The Ussing chamber provides a physiological system to measure the transport of ions, nutrients, and drugs across various epithelial tissues. One of the most studied epithelia is the intestine, which has provided several landmark discoveries regarding the ...

Abstract	The Ussing chamber provides a physiological system to measure the transport of ions, nutrients, and drugs across various epithelial tissues. One of the most studied epithelia is the intestine, which has provided several landmark discoveries regarding the mechanisms of ion transport processes. Adaptation of this method to mouse intestine adds the dimension of investigating genetic loss or gain of function as a means to identify proteins or processes affecting transepithelial transport. In this review, the principles underlying the use of Ussing chambers are outlined including limitations and advantages of the technique. With an emphasis on mouse intestinal preparations, the review covers chamber design, commercial equipment sources, tissue preparation, step-by-step instruction for operation, troubleshooting, and examples of interpretation difficulties. Specialized uses of the Ussing chamber such as the pH stat technique to measure transepithelial bicarbonate secretion and isotopic flux methods to measure net secretion or absorption of substrates are discussed in detail, and examples are given for the adaptation of Ussing chamber principles to other measurement systems. The purpose of the review is to provide a practical guide for investigators who are new to the Ussing chamber method.
MeSH term(s)	Animals ; Biological Transport/physiology ; Colon/physiology ; Duodenum/physiology ; Intestinal Absorption/physiology ; Intestinal Mucosa/physiology ; Intestines/physiology ; Mice ; Organ Culture Techniques/instrumentation ; Organ Culture Techniques/methods
Language	English
Publishing date	2009-04-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	603840-2
ISSN	1522-1547 ; 0193-1857
ISSN (online)	1522-1547
ISSN	0193-1857
DOI	10.1152/ajpgi.90649.2008
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Article ; Online: Improving the Prescription of Oral Anticoagulants in Atrial Fibrillation: A Systematic Review.

Pritchett, Ruth V / Bem, Danai / Turner, Grace M / Thomas, G Neil / Clarke, Joanne L / Fellows, Rebecca / Lane, Deirdre A / Jolly, Kate

Thrombosis and haemostasis

2019 Volume 119, Issue 2, Page(s) 294–307

Abstract: Objective: Oral anticoagulant (OAC) prescription for stroke prevention in atrial fibrillation (AF) patients frequently does not follow current guidelines, with underuse in patients at high risk of stroke and substantial overuse in those at low risk. ... ...

Abstract	Objective: Oral anticoagulant (OAC) prescription for stroke prevention in atrial fibrillation (AF) patients frequently does not follow current guidelines, with underuse in patients at high risk of stroke and substantial overuse in those at low risk. This review aims to systematically evaluate the effectiveness of interventions to improve appropriate OAC prescription in eligible AF patients for stroke prevention. Methods: Systematic review of controlled and uncontrolled studies published up to July 2017 with interventions designed to improve appropriate OAC prescription for stroke prevention in eligible AF patients (according to risk assessment tool or guidelines). Categorization of intervention types was pre-specified. The main outcome was change in proportion of eligible AF patients prescribed OACs for stroke prevention. Results: Twenty studies conducted in 392 settings were included (cluster randomized controlled trials, controlled trials and uncontrolled before-after designs; Conclusion: Interventions designed to improve appropriate prescription of OACs in eligible AF patients for stroke prevention can be effective. Successful approaches include education of HCPs; implementation of local guidelines; interdisciplinary medical care programs educating both HCPs and patients and persuasive interventions utilizing peer-group experts. Protocol registration: PROSPERO (CRD42016039654).
MeSH term(s)	Administration, Oral ; Anticoagulants/therapeutic use ; Atrial Fibrillation/drug therapy ; Cluster Analysis ; Follow-Up Studies ; Humans ; Observational Studies as Topic ; Randomized Controlled Trials as Topic ; Risk Assessment ; Risk Factors ; Stroke/prevention & control ; Treatment Outcome
Chemical Substances	Anticoagulants
Language	English
Publishing date	2019-01-22
Publishing country	Germany
Document type	Journal Article ; Systematic Review
ZDB-ID	518294-3
ISSN	2567-689X ; 0340-6245
ISSN (online)	2567-689X
ISSN	0340-6245
DOI	10.1055/s-0038-1676835
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Article ; Online: Phosphodiesterase 5 inhibitors and cystic fibrosis: correcting chloride channel dysfunction.

Clarke, Lane L

American journal of respiratory and critical care medicine

2007 Volume 177, Issue 5, Page(s) 469–470

MeSH term(s)	Animals ; Chlorides/metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Disease Models, Animal ; Imidazoles/pharmacokinetics ; Membrane Potentials/drug effects ; Mice ; Mice, Inbred CFTR ; Phosphodiesterase 5 Inhibitors ; Phosphodiesterase Inhibitors/pharmacokinetics ; Piperazines/pharmacokinetics ; Protein Modification, Translational/drug effects ; Purines/pharmacokinetics ; Sildenafil Citrate ; Sulfones/pharmacokinetics ; Triazines/pharmacokinetics ; Vardenafil Dihydrochloride
Chemical Substances	Chlorides ; Imidazoles ; Phosphodiesterase 5 Inhibitors ; Phosphodiesterase Inhibitors ; Piperazines ; Purines ; Sulfones ; Triazines ; Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6) ; Vardenafil Dihydrochloride (5O8R96XMH7) ; Sildenafil Citrate (BW9B0ZE037)
Language	English
Publishing date	2007-11-08
Publishing country	United States
Document type	Comment ; Editorial
ZDB-ID	1180953-x
ISSN	1535-4970 ; 0003-0805 ; 1073-449X
ISSN (online)	1535-4970
ISSN	0003-0805 ; 1073-449X
DOI	10.1164/rccm.200712-1805ED
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