standardized-measurement-nasal-membrane-transepithelial-potential

Standardized Measurement of Nasal Membrane Transepithelial Potential Difference (NPD)

We describe a standardized measurement of nasal potential difference (NPD). In this technique, cystic fibrosis transmembrane conductance regulator (CFTR) ...

Hadassah Hebrew University Medical Center, Jerusalem

Helicobacter pylori infection is probably acquired in childhood and causes a vigorous immune response. It is unclear why only a subgroup of infected children develops peptic ulcer disease. We have previously reported that iceA1 strains tend to be associated with duodenal disease in children. However, the pathogenesis probably does not depend solely on the H pylori strain but also on the variability of the host response.

Combination of Helicobacter pylori strain and tumor necrosis factor-alpha polymorphism of the host increases the risk of peptic ulcer disease in children.

This review focuses on the pathobiology of the gastrointestinal and hepatic manifestations of cystic fibrosis (CF) disease in relation to their genetic basis in mutations of the CF transmembrane conductance regulator (CFTR) gene. It reviews the nature of the CFTR protein, a categorization of the types of gene mutations underlying CF's various manifestations, and the ways in which absent or reduced CFTR produces various functional abnormalities in the different organs affected by CF. Subsequently, the particular organ-related clinical manifestations of CF directly associated with loss of CFTR function are addressed. Thereafter, the review discusses some of the complexities of the genotype-phenotype relationships related to milder mutations or complex genetic disorders in which CFTR abnormalities interact with other genetic and environmental factors, and the potential diagnostic roles of sweat testing or other electrophysiologic testing. This discussion examines secondary gastrointestinal manifestations of CF and the particular cases of diseases that may be related to abnormalities of CFTR.

Patterns of gastrointestinal disease associated with mutations of CFTR.

In the 21 years since the discovery of the gene that causes cystic fibrosis, our knowledge of how mutations in this gene cause the varied pathophysiological manifestations of this disease has increased substantially. This knowledge has led to the possibility of new therapeutic approaches aimed at the basic defect. This article summarizes our current knowledge of mutation-specific therapy, and focuses on orally bioavailable potentiators and correctors and suppressors of premature termination codons, including preclinical model systems and clinical trials in cystic fibrosis.

Small molecules to treat cystic fibrosis.

In a subset of patients with cystic fibrosis (CF), nonsense mutations (premature stop codons) disrupt production of full-length, functional CF transmembrane conductance regulator (CFTR). Ataluren (PTC124) allows ribosomal readthrough of premature stop codons in mRNA. We evaluated drug activity and safety in patients with nonsense mutation CF who took ataluren three times daily (morning, midday and evening) for 12 weeks at either a lower dose (4, 4 and 8 mg·kg(-1)) or higher dose (10, 10 and 20 mg·kg(-1)). The study enrolled 19 patients (10 males and nine females aged 19-57 yrs; dose: lower 12, higher seven) with a classic CF phenotype, at least one CFTR nonsense mutation allele, and an abnormal nasal total chloride transport. Both ataluren doses were similarly active, improving total chloride transport with a combined mean change of -5.4 mV (p<0.001), and on-treatment responses (at least -5 mV improvement) and hyperpolarisations (values more electrically negative than -5 mV) in 61% (p<0.001) and 56% (p = 0.002) of patients. CFTR function was greater with time and was accompanied by trends toward improvements in pulmonary function and CF-related coughing. Adverse clinical and laboratory findings were uncommon and usually mild. Chronic ataluren administration produced time-dependent improvements in CFTR activity and clinical parameters with generally good tolerability.

Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis.

Cystic fibrosis (CF) is the most common lethal monogenic disorder. Life expectancy is rising towards a mean of 40 years, with advances in all aspects of therapy apart from treating the basic defect. Since the discovery of the gene that causes CF, our knowledge of how mutations in this gene cause the varied pathophysiological manifestations of this disease has increased substantially.

New drugs for cystic fibrosis.

Cystic fibrosis (CF) is the most common lethal monogenic disorder. Life expectancy of CF patients is rising towards a mean of 40 years with advances in all aspects of therapy apart from treating the basic molecular defect. In the twenty three years since the discovery of the gene that causes cystic fibrosis, our knowledge of how mutations in this gene cause the varied pathophysiological manifestations of this disease has increased substantially. This knowledge has led to the possibility of new therapeutic approaches aimed at the basic defect. Apart from gene therapy, several novel compounds have recently been discovered using high-throughput screening which appear promising enough to develop into effective drugs to cure the basic defect. This article will summarize our current knowledge of mutation specific therapy and will focus on orally bioavailable potentiators and correctors and suppressors of premature termination codons. Further development of these drugs will enable treatment of the basic defect in diseases like CF and open the door for treatment of disease according to gene sequencing -- true personalized medicine.

Novel therapeutic approaches for cystic fibrosis.

The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gating mutation G551D prevents sufficient ion transport due to reduced channel-open probability. Ivacaftor, an oral CFTR potentiator, increases the channel-open probability.

Nutritional Status Improved in Cystic Fibrosis Patients with the G551D Mutation After Treatment with Ivacaftor.

Malnutrition is both a frequent feature and a comorbidity of cystic fibrosis (CF), with nutritional status strongly associated with pulmonary function and survival. Nutritional management is therefore standard of care in CF patients. ESPEN, ESPGHAN and ECFS recommended guidelines to cover nutritional management of patients with CF.

ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis.

Introduction.

Advancing the GI frontier for patients with CF.

Cystic fibrosis: a gastrointestinal cancer syndrome.

The etiology of primary sclerosing cholangitis (PSC) is unknown. PSC and Cystic Fibrosis related liver disease have common features: chronic inflammation, biliary damage and similar cholangiographic findings. It is unknown whether or not PSC is related to cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. We hypothesize that a sub-group of PSC patients may be a "single-organ" presentation of CF.

Article	Year
Combination of Helicobacter pylori strain and tumor necrosis factor-alpha polymorphism of the host increases the risk of peptic ulcer disease in children. Journal of pediatric gastroenterology and nutrition\| PubMed ID: 17667716	2007
Patterns of gastrointestinal disease associated with mutations of CFTR. Current gastroenterology reports\| PubMed ID: 18625144	2008
Small molecules to treat cystic fibrosis. Proceedings of the American Thoracic Society\| PubMed ID: 21030520	2010
Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis. The European respiratory journal\| PubMed ID: 21233271	2011
New drugs for cystic fibrosis. Expert opinion on investigational drugs\| PubMed ID: 21745147	2011
Novel therapeutic approaches for cystic fibrosis. Discovery medicine\| PubMed ID: 23449115	2013
Nutritional Status Improved in Cystic Fibrosis Patients with the G551D Mutation After Treatment with Ivacaftor. Digestive diseases and sciences\| PubMed ID: 26250833	2016
ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis. Clinical nutrition (Edinburgh, Scotland)\| PubMed ID: 27068495	2016
Introduction. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society\| PubMed ID: 28986025	2017
Advancing the GI frontier for patients with CF. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society\| PubMed ID: 29208346	2018
Cystic fibrosis: a gastrointestinal cancer syndrome. The Lancet. Oncology\| PubMed ID: 29706381	2018
Primary sclerosing cholangitis is associated with abnormalities in CFTR. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society\| PubMed ID: 29807875	2018

Michael Wilschanski

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