Role for animal models in understanding essential fatty acid deficiency in cystic fibrosis.

Essential fatty acid deficiency has been observed in most patients with Cystic Fibrosis (CF); however, pancreatic supplementation does not restore the deficiency, suggesting a different pathology independent of the pancreas. At this time, the underlying pathological mechanisms are largely unknown. Essential fatty acids are obtained from the diet and processed by organs including the liver and intestine, two organs significantly impacted by mutations in the cystic fibrosis transmembrane conductance regulator gene (Cftr). There are several CF animal models in a variety of species that have been developed to investigate molecular mechanisms associated with the CF phenotype. Specifically, global and systemic mutations in Cftr which mimic genotypic changes identified in CF patients have been generated in mice, rats, sheep, pigs and ferrets. These mutations produce CFTR proteins with a gating defect, trafficking defect, or an absent or inactive CFTR channel. Essential fatty acids are critical to CFTR function, with a bidirectional relationship between CFTR and essential fatty acids proposed. Currently, there are limited analyses on the essential fatty acid status in most of these animal models. Of interest, in the mouse model, essential fatty acid status is dependent on the genotype and resultant phenotype of the mouse. Future investigations should identify an optimal animal model that has most of the phenotypic changes associated with CF including the essential fatty acid deficiencies, which can be used in the development of therapeutics.

Factors Contributing to Vitamin D Status at Hospital Admission for Pulmonary Exacerbation in Adults With Cystic Fibrosis.

BACKGROUND: Individuals with cystic fibrosis (CF) have difficulty maintaining optimal vitamin D status due to pancreatic insufficiency-induced malabsorption, inadequate sunlight exposure, and poor intake of vitamin D containing foods. Vitamin D deficiency may increase the risk of pulmonary exacerbations of CF. The objective of this study was to assess factors impacting vitamin D status in patients with CF recently hospitalized for a pulmonary exacerbation of CF. METHODS: This was a pre-planned analysis of vitamin D intake in patients enrolled in a multi-center, double-blind, randomized controlled study examining vitamin D therapy for pulmonary exacerbation of CF. Demographic information, responses from a habitual sun exposure questionnaire and food frequency questionnaire, and vitamin D supplement usage were queried and compared to serum 25-hydroxyvitamin D (25(OH)D) concentrations. RESULTS: A total of 48 subjects were included in this analysis. Subjects were taking approximately 1,200 IU of vitamin D daily. Reported vitamin D intake, age, race, employment, and education were not significantly associated with vitamin D status in this population. However, smoking status, sunlight exposure in the last 3 years, and skin type (in the bivariate model) were all significantly associated with vitamin D status (all p<0.05). CONCLUSIONS: Sunlight exposure was the most predictive determinant of vitamin D status in patients with CF prior to pulmonary exacerbation. Subjects reported vitamin D intake below the recommended amounts. The role and mode of optimizing vitamin D status prior to a pulmonary exacerbation needs further investigation.

[Mucoviscidosis, a challenging medical problem]. / Mukovistsidoz ­ aktual'naya problema meditsiny.

The authors present the currently available data on mucoviscidosis (cystic fibrosis) based on their original experience and the review of the relevant literature. Special attention is given to the pathogenetic mechanisms underlying the development of this condition, its diagnostics, and methods of treatment as exemplified by the clinical case of cystic fibrosis in an adult patient.

Modulation of the maladaptive stress response to manage diseases of protein folding.

Diseases of protein folding arise because of the inability of an altered peptide sequence to properly engage protein homeostasis components that direct protein folding and function. To identify global principles of misfolding disease pathology we examined the impact of the local folding environment in alpha-1-antitrypsin deficiency (AATD), Niemann-Pick type C1 disease (NPC1), Alzheimer's disease (AD), and cystic fibrosis (CF). Using distinct models, including patient-derived cell lines and primary epithelium, mouse brain tissue, and Caenorhabditis elegans, we found that chronic expression of misfolded proteins not only triggers the sustained activation of the heat shock response (HSR) pathway, but that this sustained activation is maladaptive. In diseased cells, maladaptation alters protein structure-function relationships, impacts protein folding in the cytosol, and further exacerbates the disease state. We show that down-regulation of this maladaptive stress response (MSR), through silencing of HSF1, the master regulator of the HSR, restores cellular protein folding and improves the disease phenotype. We propose that restoration of a more physiological proteostatic environment will strongly impact the management and progression of loss-of-function and gain-of-toxic-function phenotypes common in human disease.

Aspergilosis broncopulmonar alérgica en pediatría / Allergic bronchopulmonary aspergillosis in childhood

La aspergilosis broncopulmonar alérgica (ABPA) es una complicación importante en niños portadores de asma atópica, fibrosis quística (FQ) y otras enfermedades pulmonares crónicas asociadas a bronquiectasias. Esta afección es el resultado de la colonización de la vía aérea por Aspergilus, habitualmente fumigatus, produce una reacción de hipersensibilidad tipo Th2CD4 con la producción de IgE total y específica. El diagnóstico debe sospecharse en pacientes que presenten secreciones bronquiales en moldes café, aparición o aumento de sibilancias, infiltrados pulmonares y reducción de la función pulmonar. Si esta afección no es tratada precozmente puede conducir a un severo deterioro de la función pulmonar y a largo plazo llegar a la fibrosis. El diagnóstico es difícil debido a la sobreposición de las manifestaciones clínicas y radiológicas de la ABPA con exacerbaciones pulmonares producidas por bacterias o virus. Se han sugerido criterios para establecer el diagnóstico; en este sentido la IgE total y específica son los más importantes. Últimamente han sido desarrollados nuevos test serológicos con el objeto de mejorar la detección precoz y monitorización de la ABPA, presentando gran sensibilidad y especificidad. El tratamiento consiste en el uso de corticoides sistémicos. El itraconazol parece mejorar el control de la enfermedad y reducir la dosis de corticoides.

[Haemolytic anaemia and a clotting disorder as first signs of cystic fibrosis in two infants]. / Hemolytische anemie en een stollingsstoornis als eerste manifestatie van cystische fibrose bij twee zuigelingen.

2 infants, a boy aged 8 weeks and a girl aged 5 months, presented with symptoms of fat-soluble vitamin deficiencies. The first infant had frequently voluminous bowel movements, anaemia and was not thriving; he had anaemia due to vitamin-E deficiency. The second infant had multiple haematomas on the trunk and legs due to a vitamin-K deficiency-related clotting disorder. The sweat test was positive in both cases, confirming the diagnosis of cystic fibrosis. The infants were treated with supplementary pancreatic enzymes and fat-soluble vitamins A, D, E and K. Cystic fibrosis rarely presents with symptoms of fat-soluble vitamin deficiency. However, in cases of unexplained haemolytic anaemia or haemorrhagic disorder due to vitamin E or K deficiencies, respectively, cystic fibrosis should be considered as a possible cause.

Knowledge, interests and educational needs of adults diagnosed with cystic fibrosis after age 18.

BACKGROUND: Little is known about the knowledge, interests, or educational needs of those diagnosed with cystic fibrosis (CF) as adults or the extent to which they find available information helpful. The purpose of this inquiry was to address these gaps. METHODS: A mailed survey, completed by an international sample (N=130) recruited through internet sites and CF Centers, collected quantitative and qualitative data to address five research questions. A response rate of 74.3% was achieved. RESULTS: Most participants (67.4%) said they knew little or nothing about CF at diagnosis. Of the 71.5% who indicated they received patient education, 26.9% felt they were given 'too little'. At diagnosis, most wanted disease-related information about CF. Over time they expressed interest in topics related to quality-of-life, such as CF research efforts, alternative medicine and employment issues. Three-fourths (75.4%) were active information seekers, but 60.2% were less than satisfied with what they found. Qualitative responses indicated participants did not 'see themselves' in available materials, which many described as 'depressing'. CONCLUSIONS: Medical caregivers must be aware of and respond to the unique educational interests and needs of their adult-diagnosed patients. Additional research is recommended to better understand how patient education benefits these adults.

Plasma vitamin C concentrations in patients with cystic fibrosis: evidence of associations with lung inflammation.

Vitamin C status and possible associations with the disease process in cystic fibrosis (CF) patients were investigated. Plasma vitamin C concentrations in patients from two different mid-European populations (Swiss, n = 62; Austrian, n = 60) taking no or low-dose vitamin C from multivitamin supplements did not differ from each other or from control subjects (n = 34). Vitamin C concentrations decreased with age (5.05 mumol.L-1, y-1). When followed up for 12 mo, patients had the highest plasma vitamin C concentrations in February and the lowest in May and August (P < 0.01); the decrease in vitamin C was accompanied by increases in plasma malondialdehyde (P < 0.001) and tumor necrosis factor alpha concentrations (P < 0.01). During supplementation with vitamin E for 2 mo or beta-carotene for 12 mo vitamin C concentrations did not change. They correlated inversely with white blood cell count (r = -0.36, P = 0.008), bands (r = -0.36, P = 0.02), alpha 1-acid glycoprotein (r = -0.45, P = 0.002), interleukin 6 (r = -0.46, P = 0.0006), and neutrophil elastase/alpha 1-proteinase inhibitor complexes (r = -0.34, P = 0.02). In patients with vitamin C concentrations < 40 mumol/L, all indexes of inflammation were relatively high, whereas those with concentrations > 80 mumol/L (upper quartile of control subjects) showed clearly lower values. These results are consistent with the hypothesis that by scavenging oxygen free radicals vitamin C interacts with an inflammation-amplifying cycle of activation of alveolar macrophages and neutrophils, release of proinflammatory cytokines and oxygen free radicals, and inactivation of antiproteases.

Common denominators in the etiology and pathology of visceral lesions of cystic fibrosis and Keshan disease.

The common denominator of a unique disseminated multi-focal miliary myocardial hyaline necrosis and fibrosis in Keshan disease (KSD) and cystic fibrosis (CF) and a commonality of the affected age groups of fetuses and preschool children led to the review of existing KSD autopsy material to search for pancreatic and hepatic lesions considered pathognomonic for CF. Pancreatic lesions considered pathognomonic for CF were found in 595, or 35% of 1700 documented cases of KSD. The pancreatic lesions were limited to tissues of fetuses and preschool children. Adults dying of KSD had diagnostic lesions limited to the cardiovascular system, liver, and skeletal muscle. Varying degrees of focal biliary cirrhosis were identified in 850, or 50% of the KSD autopsies, and 85, or 5% developed severe lobular cirrhosis. The common denominator in CF and KSD appears to be a primary or induced secondary selenium deficiency in age-susceptible humans, prenatally at or around 22 wk of fetal life, during early postnatal life, or during the rapid-growth preschool years. The basic difference between the natural history of CF and KSD is that the selenium deficiency is totally environmental in KSD and appears to be the result of a maternal malabsorptive syndrome or an abnormality of selenium transfer in CF.

Hydroxyapatite in the pathogenesis of cystic fibrosis.

Submandibular saliva collected from cystic fibrosis patients and control subjects was separated by centrifugation into an insoluble deposit and a clear supernatant. The resulting calcium and phosphorus analyses performed on both fractions warranted a closer investigation as a consistent Ca/P molar ratio of 1.5 was found in the deposit of the cystic fibrosis patients, while no consistent ratio >1.0 was found in the deposit of the control subjects. The expected result, that calcium and phosphorus in the deposit of cystic fibrosis patients is present as the solid phase of hydroxyapatite, was confirmed by a detailed comparison of x-ray powder diffraction patterns of an ashed sample of this deposit and a similarly treated synthetic sample of hydroxyapatite.