Publications by authors named "Geneviève Mailhot"

40 Publications

Combined Indeterminate and Impaired Glucose Tolerance Is a Novel Group at High Risk of Cystic Fibrosis-Related Diabetes.

J Clin Endocrinol Metab 2021 09;106(10):e3901-e3910

Montreal Clinical Research Institute, Montréal, Québec, Canada.

Background: Indeterminate glycemia (INDET) and impaired glucose tolerance (IGT) are independently associated with cystic fibrosis-related diabetes (CFRD) risk. We determined whether patients meeting both criteria have increased risk of diabetes in 2 separate adult cohorts.

Methods: The Montreal Cystic Fibrosis Cohort (MCFC; n = 293 baseline and 198 for prospective analysis excluding subjects identified with incident CFRD at baseline) and the Lyon cystic fibrosis cohort [Determination of the Predictive Factors in the Reversibility or the Aggravation in the Disorders of the Glucose Metabolism in Cystic Fibrosis Patients (DIAMUCO); n = 144/105] are prospective observational cohorts.

Results: In the MCFC and DIAMUCO cohorts, mean age was 25.5 ± 7.7 and 25.0 ± 8.6 years; body mass index, 21.7 ± 3.0 and 20.2 ± 2.2 kg/m2; percentage of forced expiratory volume expired in 1 sec, 73.2 ± 22.1 and 62.5 ± 21.9; and follow-up, 6.9 ± 3.8 and 2.4 ± 1.2 years, respectively. In the MCFC cohort, the IGT only and combined INDET and IGT (INDET + IGT) groups had greater risk of CFRD (P = 0.0109). In the DIAMUCO cohort, there was lower diabetes-free survival in the INDET + IGT group (P = 0.0105). In both cohorts, CFRD risk ranged from 17% in normal glucose tolerance patients up to 42% to 56% in patients with INDET + IGT.

Conclusion: Patients who meet combined criteria have a higher risk of developing diabetes probably justifying closer follow-up.
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http://dx.doi.org/10.1210/clinem/dgab384DOI Listing
September 2021

Long-term bone mineral density changes and fractures in lung transplant recipients with cystic fibrosis.

J Cyst Fibros 2021 05 21;20(3):525-532. Epub 2020 Oct 21.

Department of Nutrition, Faculty of Medicine, Université de Montreal, 2405 Cote Sainte-Catherine Rd, Montreal, Quebec H3T 1A8, Canada; Research Centre, CHU Sainte-Justine, 3175 Cote Sainte-Catherine Rd, Montreal, Quebec H3T 1C5, Canada. Electronic address:

Background: Little is known about long-term bone mineral density (BMD) changes and fractures in lung transplant recipients with cystic fibrosis (CF). We examined femur and lumbar spine (LS) BMD changes in men and women with CF up to 10 years post-transplant and documented post-transplant fracture prevalence.

Methods: Retrospective study of individuals who had undergone a lung transplant (2000-2015) and had a pre-transplant and at least one BMD measurement after transplant. Vertebral fractures were assessed on chest computed tomography scans and other fractures abstracted from medical records.

Results: The cohort consisted of 131 individuals; 53% males, median age: 28 years [interquartile range: 24-35] and 31% having pre-transplant low bone mass. Most recipients were given bisphosphonates after transplant with proportion reaching 94% at 10 years. Up to 10 years post-transplant, men experienced positive or little change in LS BMD, indicating minimal loss from pre-transplant values. In contrast, women displayed negative changes in BMD up to 5 years post-transplant before recovering pre-transplant BMD values by 10 years. Similar patterns were observed at the femur BMD where men demonstrated a lower bone loss and faster recovery towards pre-transplant values than women. After transplant, 88% of recipients maintained their pre-transplant bone status, 3% experienced an improvement, mostly progressing from low bone mass to normal status whereas 9% had a deterioration of their pre-transplant bone status. Twenty-seven recipients suffered fractures in the post-transplant period.

Conclusions: These findings underline that lung recipients with CF remain at risk of skeletal fragility despite prompt initiation of post-transplant anti-osteoporosis therapy.
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http://dx.doi.org/10.1016/j.jcf.2020.09.012DOI Listing
May 2021

Glycated Hemoglobin as a First-line Screening Test for Cystic Fibrosis‒Related Diabetes and Impaired Glucose Tolerance in Children With Cystic Fibrosis: A Validation Study.

Can J Diabetes 2021 Dec 26;45(8):768-774. Epub 2021 Mar 26.

Research Centre, CHU Sainte-Justine, Montréal, Québec, Canada; Department of Nutrition, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada. Electronic address:

Objectives: Our aims in this study were to document the screening rate for cystic fibrosis‒related diabetes (CFRD) in children followed at a cystic fibrosis (CF) clinic in Canada and to evaluate the accuracy of various glycated hemoglobin (A1C) cutoffs to screen for CFRD and impaired glucose tolerance (IGT) in a pediatric CF population.

Methods: The CFRD screening rate was calculated over a follow-up period of up to 8 years among children who attended the CF clinic between 1993 and 2018. Test performance of A1C at various thresholds ranging from 5.5% to 6.2% was compared with the oral glucose tolerance test (OGTT) as the reference method. Children with CF aged ≥10 years with an OGTT performed within 120 days of A1C measurement were included in the analysis.

Results: The overall CFRD screening rate was 53.0%. A total of 256 children were included for the A1C performance analysis, of whom 8.6% had an OGTT-confirmed CFRD diagnosis. An A1C threshold of 5.8% demonstrated an optimal balance between sensitivity (90.9%) and specificity (60.7%) for CFRD screening, leading to a potential reduction of 56.3% of the annual required OGTTs. A1C demonstrated poor accuracy for identifying children with IGT.

Conclusions: An A1C threshold ≥5.8% allows for identification of children requiring further CFRD investigations, which may reduce the clinical burden of children with CF without compromising the ability of early CFRD diagnosis.
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http://dx.doi.org/10.1016/j.jcjd.2021.03.005DOI Listing
December 2021

Comparison of two vitamin D supplementation strategies in children with sickle cell disease: a randomized controlled trial.

Br J Haematol 2021 01 10;192(2):385-394. Epub 2020 Nov 10.

Department of Nutrition, Université de Montréal, Montreal, Quebec, Canada.

Previously, we showed that nearly 70% of children followed in our sickle cell disease (SCD) clinic were vitamin D- deficient and had low vitamin intake with poor use of supplements. We compared the change in serum 25-hydroxyvitamin D [25(OH)D], safety and clinical impact of two vitamin D supplementation regimens in children with SCD. Children (5-17 years, all genotypes) were randomized to a single bolus of vitamin D (300 000 IU; n = 18) or placebo (n = 20). All children received a prescription for daily 1 000 IU vitamin D . Serum 25(OH)D and calcium, urinary calcium/creatinine ratio, musculoskeletal pain, quality of life, haematology and bone markers were assessed at baseline and three months post intervention. Bolus administration led to a greater rise in 25(OH)D levels from baseline compared to placebo (20 ± 16 nmol/l vs. 2 ± 19 nmol/l; P = 0·003) and correction of vitamin D deficiency. No hypercalcaemia nor hypercalciuria occurred during the study, but more children in the bolus group experienced gastrointestinal symptoms within the first month (P = 0·04). There were no differences between groups for other outcomes. The use of a high-dose vitamin D bolus combined with daily 1 000 IU vitamin D was more efficient in raising 25(OH)D levels than daily supplementation alone in children with SCD.
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http://dx.doi.org/10.1111/bjh.17119DOI Listing
January 2021

Abnormal glucose tolerance in a pediatric cystic fibrosis cohort: Trends in clinical outcomes and associated factors in the preceding years.

Nutr Metab Cardiovasc Dis 2021 01 8;31(1):277-285. Epub 2020 Aug 8.

Research Centre, CHU Sainte-Justine, 3175 Cote Sainte-Catherine Rd, Montreal, Quebec H3T 1C5, Canada; Department of Nutrition, Faculty of Medicine, Université de Montreal, 2405 Cote Sainte-Catherine Rd, Montreal, Quebec H3T 1A8, Canada. Electronic address:

Background And Aims: Deterioration of anthropometric and lung function parameters was shown to precede the onset of cystic fibrosis-related diabetes (CFRD) in adults. In children, studies have been conducted in small cohorts with relatively short observation period. Study objectives were to document the longitudinal trends of anthropometric, pulmonary, nutritional and metabolic parameters from cystic fibrosis (CF) diagnosis to the ascertainment of abnormal glucose tolerance and identify parameters associated with the incidence of such abnormalities in a pediatric CF cohort.

Methods And Results: Retrospective cohort study of 281 children with CF. Longitudinal trends of anthropometric, lung function, nutritional and metabolic data were generated from CF diagnosis to the ascertainment of abnormal glucose tolerance defined as the presence of either impaired glucose tolerance (IGT), unconfirmed CFRD or CFRD. Cox models and Kaplan-Meier curves were used to identify factors associated with developing abnormal glucose tolerance. Forty-five percent of cohort had normal glucose tolerance (NGT), 27% IGT, 10% unconfirmed CFRD and 18% CFRD. Children who developed CFRD displayed lower height z-scores from a very early age. Conversely, HbA1c levels began to rise closer to CFRD ascertainment. Height z-scores (HR: 0.45; CI 95% [0.29-0.69]) and HbA1c (HR: 2.43; CI 95% [1.86-3.18]) in years preceding ascertainment were associated with the risk of developing CFRD.

Conclusion: Children who developed CFRD display distinctive trends for height z-scores from a very early age, whereas HbA1c appears as a marker of established glucose metabolism derangements.
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http://dx.doi.org/10.1016/j.numecd.2020.07.044DOI Listing
January 2021

Vitamin D and Immunity in Infants and Children.

Nutrients 2020 Apr 27;12(5). Epub 2020 Apr 27.

Department of Physiology, McGill University, Montreal, Quebec, H3G 1Y6, Canada.

The last couple of decades have seen an explosion in our interest and understanding of the role of vitamin D in the regulation of immunity. At the molecular level, the hormonal form of vitamin D signals through the nuclear vitamin D receptor (VDR), a ligand-regulated transcription factor. The VDR and vitamin D metabolic enzymes are expressed throughout the innate and adaptive arms of the immune system. The advent of genome-wide approaches to gene expression profiling have led to the identification of numerous VDR-regulated genes implicated in the regulation of innate and adaptive immunity. The molecular data infer that vitamin D signaling should boost innate immunity against pathogens of bacterial or viral origin. Vitamin D signaling also suppresses inflammatory immune responses that underlie autoimmunity and regulate allergic responses. These findings have been bolstered by clinical studies linking vitamin D deficiency to increased rates of infections, autoimmunity, and allergies. Our goals here are to provide an overview of the molecular basis for immune system regulation and to survey the clinical data from pediatric populations, using randomized placebo-controlled trials and meta-analyses where possible, linking vitamin D deficiency to increased rates of infections, autoimmune conditions, and allergies, and addressing the impact of supplementation on these conditions.
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http://dx.doi.org/10.3390/nu12051233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282029PMC
April 2020

Impact of a dietitian-led counseling program to support transition to whole foods during oral immunotherapy.

J Allergy Clin Immunol Pract 2020 06 26;8(6):2107-2109.e3. Epub 2020 Feb 26.

Sainte-Justine University Hospital Research Center, Montreal, Quebec, Canada; Allergy Section, Department of Pediatrics, Sainte-Justine University Hospital Center, Montreal, Quebec, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2020.02.014DOI Listing
June 2020

CFTR deletion affects mouse osteoblasts in a gender-specific manner.

J Cell Physiol 2020 10 27;235(10):6736-6753. Epub 2020 Jan 27.

Research Centre, CHU Sainte-Justine, Montreal, Montreal, Quebec, Canada.

Advancements in research and care have contributed to increase life expectancy of individuals with cystic fibrosis (CF). With increasing age comes a greater likelihood of developing CF bone disease, a comorbidity characterized by a low bone mass and impaired bone quality, which displays gender differences in severity. However, pathophysiological mechanisms underlying this gender difference have never been thoroughly investigated. We used bone marrow-derived osteoblasts and osteoclasts from Cftr and Cftr mice to examine whether the impact of CF transmembrane conductance regulator (CFTR) deletion on cellular differentiation and functions differed between genders. To determine whether in vitro findings translated into in vivo observations, we used imaging techniques and three-point bending testing. In vitro studies revealed no osteoclast-autonomous defect but impairment of osteoblast differentiation and functions and aberrant responses to various stimuli in cells isolated from Cftr females only. Compared with wild-type controls, knockout mice exhibited a trabecular osteopenic phenotype that was more pronounced in Cftr males than Cftr females. Bone strength was reduced to a similar extent in knockout mice of both genders. In conclusion, we find a trabecular bone phenotype in Cftr mice that was slightly more pronounced in males than females, which is reminiscent of the situation found in patients. However, at the osteoblast level, the pathophysiological mechanisms underlying this phenotype differ between males and females, which may underlie gender differences in the way bone marrow-derived osteoblasts behave in absence of CFTR.
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http://dx.doi.org/10.1002/jcp.29568DOI Listing
October 2020

Vitamin D in the prevention of exacerbations of asthma in preschoolers (DIVA): protocol for a multicentre randomised placebo-controlled triple-blind trial.

BMJ Open 2019 12 30;9(12):e033075. Epub 2019 Dec 30.

Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.

Introduction: Preschoolers have the highest rate of emergency visits and hospitalisations for asthma exacerbations of all age groups, with most triggered by upper respiratory tract infections (URTIs) and occurring in the fall or winter. Vitamin D insufficiency is highly prevalent in Canadian preschoolers with recurrent asthma exacerbations, particularly in winter. It is associated with more URTIs and, in patients with asthma, more oral corticosteroid (OCS) use. Although evidence suggests that vitamin D supplements significantly decrease URTIs and asthma exacerbations requiring OCS, there is insufficient data in preschoolers. This study aims to determine the impact of vitamin D supplementation on exacerbations requiring OCS, in preschoolers with recurrent URTI-induced asthma exacerbations.

Methods And Analysis: This is a phase III, randomised, triple-blind, placebo-controlled, parallel-group multicentre trial of vitamin D supplementation in children aged 1-5 years, with asthma triggered by URTIs and a recent history of frequent URTIs and OCS use. Children (n=865) will be recruited in the fall and early winter and followed for 7 months. They will be randomised to either the (1) intervention: two oral boluses of 100 000 international unit (IU) vitamin D (3.5 months apart) with 400 IU vitamin D daily; or (2) control: identical placebo boluses with daily placebo. The primary outcome is the number of exacerbations requiring OCS per child, documented by medical and pharmacy records. Secondary outcomes include number of laboratory-confirmed viral URTIs, exacerbation duration and severity, parent functional status, healthcare use, treatment deintensification, cost and safety.

Ethics And Dissemination: This study has received ethical approval from all sites. Results will be disseminated via international conferences and manuscripts targeting paediatricians and respirologists, and to families of asthmatic children via our Quebec parents-partners outreach programme. If proven effective, findings may markedly influence the management of URTI-induced asthma in high-morbidity preschoolers and could be directly implemented into practice with an update to clinical guidelines.

Trial Registration Number: NCT03365687.
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http://dx.doi.org/10.1136/bmjopen-2019-033075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955525PMC
December 2019

Trends, Determinants, and Impact on Survival of Post-Lung Transplant Weight Changes: A Single-center Longitudinal Retrospective Study.

Transplantation 2019 12;103(12):2614-2623

Department of Nutrition, Faculty of Medicine, Université de Montreal, Montreal, Canada.

Background: Weight gain is commonly seen in lung transplant (LTx) recipients. Although previous studies have focused on weight changes at fixed time periods and relatively early after transplant, trends over time and long-term weight evolution have not been described in this population. The study objectives were to document weight changes up to 15 years post-LTx and assess the predictors of post-LTx weight changes and their associations with mortality.

Methods: Retrospective cohort study of LTx recipients between January 1, 2000, and November 30, 2016 (n = 502). Absolute weight changes from transplant were calculated at fixed time periods (6 mo, 1, 2, 5, 10, and 15 y), and continuous trends over time were generated. Predictors of weight changes and their association with mortality were assessed using linear and Cox regression analysis.

Results: LTx recipients experienced a gradual increase in weight, resulting from the combination of multiple weight trajectories. Interstitial lung disease diagnosis negatively predicted post-LTx weight changes at all time points, whereas transplant body mass index categories were significant predictors at earlier time points. Patients with a weight gain of >10% at 5 years had a better survival (hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.20-0.66), whereas a 10% weight loss at earlier time points was associated with worse survival (1 y: HR, 2.04; 95% CI, 1.22-3.41 and 2 y: HR, 2.37; 95% CI, 1.22-4.58).

Conclusions: Post-LTx weight changes display various trajectories, are predicted to some extent by individual and LTx-related factors, and have a negative or positive impact on survival depending on the time post-LTx. These results may lead to a better individualization of weight management after transplant.
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http://dx.doi.org/10.1097/TP.0000000000002696DOI Listing
December 2019

Association between fat-soluble nutrient status and auditory and visual related potentials in newly diagnosed non-screened infants with cystic fibrosis: A case-control study.

Prostaglandins Leukot Essent Fatty Acids 2019 11 5;150:21-30. Epub 2019 Sep 5.

Research Centre of Sainte-Justine University Health Center, Université de Montréal, Montreal, Quebec, H3T 1C5, Canada; Department of Nutrition, Université de Montréal, Montreal, Quebec, H3T 1C5, Canada. Electronic address:

Nutritional deficiencies often precede the diagnosis of cystic fibrosis (CF) in infants, and occur at a stage where the rapidly developing brain is more vulnerable to insult. We aim to compare fat-soluble nutrient status of newly diagnosed non-screened infants with CF to that of healthy infants, and explore the association with neurodevelopment evaluated by electroencephalography (EEG). Our results show that CF infants had lower levels of all fat-soluble vitamins and docosahexaenoic acid (DHA) compared to controls. The auditory evoked potential responses were higher in CF compared to controls whereas the visual components did not differ between groups. DHA levels were correlated with auditory evoked potential responses. Although resting state frequency power was similar between groups, we observed a negative correlation between DHA levels and low frequencies. This study emphasizes the need for long-term neurodevelopmental follow-up of CF infants and pursuing intervention strategies in the future.
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http://dx.doi.org/10.1016/j.plefa.2019.09.003DOI Listing
November 2019

Impact of two oral doses of 100,000 IU of vitamin D in preschoolers with viral-induced asthma: a pilot randomised controlled trial.

Trials 2019 Feb 18;20(1):138. Epub 2019 Feb 18.

Clinical Research and Knowledge Transfer Unit on Childhood Asthma, Research Centre, Sainte-Justine University Health Centre, Montreal, Quebec, Canada.

Background: New evidence supports the use of supplemental vitamin D in the prevention of exacerbation of asthma; however, the optimal posology to sufficiently raise serum levels while maximising adherence is unclear. The objective was to ascertain the efficacy of high-dose vitamin D in increasing serum vitamin D in preschoolers with asthma and provide preliminary data on safety and efficacy outcomes.

Methods: We conducted a 7-month, triple-blind, randomised, placebo-controlled, pilot trial of children aged 1-5 years with viral-induced asthma. Participants were allocated to receive two oral doses of 100,000 IU vitamin D (intervention) or identical placebo (control) 3.5 months apart, once in the fall and once in the winter. Serum 25-hydroxyvitamin D (25OHD) was measured by tandem mass spectrometry at baseline, 10 days, 3.5 months, 3.5 months + 10 days, and 7 months. The main outcome was the change in serum 25OHD from baseline (Δ25OHD) over time and at 3.5 and 7 months; other outcomes included the proportion of children with 25OHD ≥ 75 nmol/L, safety, and adverse event rates.

Results: Children (N = 47) were randomised (intervention, 23; control, 24) in the fall. There was a significant adjusted group difference in the Δ25OHD (95% confidence interval) of 57.8 (47.3, 68.4) nmol/L, p < 0.0001), with a time (p < 0.0001) and group*time interaction effect (p < 0.0001), in favour of the intervention. A significant group difference in the Δ25OHD was observed 10 days after the first (119.3 [105.8, 132.9] nmol/L) and second (100.1 [85.7, 114.6] nmol/L) bolus; it did not reach statistical significance at 3.5 and 7 months. At 3.5 and 7 months, respectively, 63% and 56% of the intervention group were vitamin D sufficient (≥ 75 nmol/L) compared to 39% and 36% of the control group. Hypercalciuria, all without hypercalcaemia, was observed in 8.7% of intervention and 10.3% of control samples at any time point. Exacerbations requiring rescue oral corticosteroids, which appear as a promising primary outcome, occurred at a rate of 0.87/child.

Conclusion: Two oral boluses of 100,000 IU vitamin Donce in the fall and once in the winter, rapidly, safely, and significantly raises overall serum vitamin D metabolites. However, it is sufficient to maintain 25OHD ≥ 75 nmol/L throughout 7 months in only slightly more than half of participants.

Trial Registration: ClinicalTrials.gov, NCT02197702 (23 072014). Registered on 23 July 2014.
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http://dx.doi.org/10.1186/s13063-019-3184-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379931PMC
February 2019

Effectiveness of two vitamin D repletion protocols on the vitamin D status of adults with a recent spinal cord injury undergoing inpatient rehabilitation: a prospective case series.

Spinal Cord Ser Cases 2018 29;4:96. Epub 2018 Oct 29.

3Center for Interdisciplinary Research in Rehabilitation (CRIR), Montreal, Quebec Canada.

Study Design: Prospective case series.

Objectives: To assess the effectiveness and safety of two vitamin D repletion protocols given to individuals with spinal cord injury (SCI).

Setting: Publicly-funded intensive inpatient rehabilitation center, Montreal, Canada.

Methods: Thirty adults with recent SCI complete or incomplete sensorimotor impairments were recruited upon admission from designated regional SCI trauma centers. Participants with serum 25OHD ≤ 30 nmol/L were given 10,000 IU of weekly and 1000 IU of daily vitamin D for 36.8 ± 11.9 days (). Subjects with serum 25OHD > 30 nmol/L received 1000 IU of daily vitamin D for 38.2 ± 11.6 days (). Outcomes were changes in 25OHD levels from baseline to the end of the study period and safety outcomes. Thresholds for vitamin D deficiency, insufficiency and sufficiency were: 25OHD levels ≤30 nmol/L, 30-74 nmol/L, and ≥75 nmol/L.

Results: At baseline, 34 and 66% of participants had serum 25OHD < 30 and >30 nmol/L. Both protocols induced a rise in serum 25OHD with a greater increase in the HD vs. LD regimen (31.4 [95% CI: 16.7, 46.0] vs. 11.7 nmol/L [95% CI: 2.2, 21.2]). None of the participants given the HD remained vitamin D deficient, but only one achieved vitamin D sufficiency. Nearly all individuals on the LD regimen remained vitamin D insufficient with only two reaching vitamin D sufficiency. No adverse effects were observed over the course of the supplementation.

Conclusions: Although 1000 IU of daily vitamin D alone or in combination with weekly 10,000 IU for an average of 37.6 days increased serum 25OHD, they were unsuccessful in improving the impaired vitamin D status during inpatient rehabilitation of individuals with a recent SCI.
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http://dx.doi.org/10.1038/s41394-018-0129-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206088PMC
October 2018

Vitamin D Intake and Status of Children With Sickle Cell Disease in Montreal, Canada.

J Pediatr Hematol Oncol 2018 11;40(8):e531-e536

Department of Nutrition, Université de Montréal.

Sickle cell disease (SCD) and vitamin D deficiency share manifestations such as bone complications and bony pains. Canadian SCD children are characterized by compromised sun exposure all year long and potential dietary deficiency, which combined to SCD-causing high nutritional demands, may lead to impaired vitamin D status. The objectives of this study were to document vitamin D status and intake and assess the relationship between vitamin D status and SCD-related outcomes in Canadian children with SCD followed in a tertiary pediatric center. Our study population included 119 children (47% males, median age [interquartile range]: 11.1 [9.2-14.8]) mainly of Haitian and Sub-Saharan African origin who had at least one measure of serum 25-hydroxyvitamin D (25OHD) performed between June 2015 and February 2017. Predominant genotypes were homozygous hemoglobin S (60%) and sickle hemoglobin-C (32%). Vitamin D deficiency (25OHD<30 nmol/L) and insufficiency (30 to 49 nmol/L) were present in 31% and 37% of children, respectively. Vitamin D-sufficient children (25OHD>50 nmol/L) had higher hemoglobin levels, lower leukocyte, reticulocyte, and neutrophil counts, compared with vitamin D-deficient and insufficient children. Vitamin D intake was low and modestly correlated to serum 25OHD levels. Acute SCD complications in the preceding 2 years were not associated with vitamin D status in these children.
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http://dx.doi.org/10.1097/MPH.0000000000001306DOI Listing
November 2018

Nutritional Requirements of Lung Transplant Recipients: Challenges and Considerations.

Nutrients 2018 Jun 19;10(6). Epub 2018 Jun 19.

Department of Nutrition, Faculty of Medicine, Université de Montreal, 2405 Cote Sainte-Catherine Rd., Montreal, QC H3T 1A8, Canada.

An optimal nutritional status is associated with better post-transplant outcomes and survival. Post-lung transplant nutrition management is however particularly challenging as lung recipients represent a very heterogeneous group of patients in terms of age, underlying diseases, weight status and presence of comorbidities. Furthermore, the post-transplant period encompasses several stages characterized by physiological and pathophysiological changes that affect nutritional status of patients and necessitate tailored nutrition management. We provide an overview of the current state of knowledge regarding nutritional requirements in the post-lung transplant period from the immediate post-operative phase to long-term follow-up. In the immediate post-transplantation phase, the high doses of immunosuppressants and corticosteroids, the goal of maintaining hemodynamic stability, the presence of a catabolic state, and the wound healing process increase nutritional demands and lead to metabolic perturbations that necessitate nutritional interventions. As time from transplantation increases, complications such as obesity, osteoporosis, cancer, diabetes, and kidney disease, may develop and require adjustments to nutrition management. Until specific nutritional guidelines for lung recipients are elaborated, recommendations regarding nutrient requirements are formulated to provide guidance for clinicians caring for these patients. Finally, the management of recipients with special considerations is also briefly addressed.
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http://dx.doi.org/10.3390/nu10060790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024852PMC
June 2018

Age-related decline of the acute local inflammation response: a mitigating role for the adenosine A receptor.

Aging (Albany NY) 2017 10;9(10):2083-2097

Faculty of Medicine, and Centre de Recherche du CHU de Québec - Université Laval, Quebec City, Canada.

Aging is accompanied by an increase in markers of innate immunity. How aging affects neutrophil functions remains of debate.The adenosine A receptor (AR), essential to the resolution of inflammation, modulates neutrophil functions. We sought to determine whether or not AR protects against the effects of aging. We monitored neutrophil influx, viability, and activation as well as cytokine accumulation in wild-type (WT) and AR-knockout mice (KO) at three different ages.Several readouts decreased with aging: neutrophil counts in dorsal air pouches (by up to 55%), neutrophil viability (by up to 56%), elastase and total protein in exudates (by up to 80%), and local levels of cytokines (by up to 90%). Each of these parameters was significantly more affected in AR-KO mice. CXCL1-3 levels were largely unaffected. The effects of aging were not observed systemically. Preventing neutrophil influx into the air pouch caused a comparable cytokine pattern in young WT mice. Gene expression (mRNA) in leukocytes was affected, with CXCL1 and CCL4 increasing and with TNF and IL-1α decreasing.Aging has deleterious effects on the acute inflammatory response and neutrophil-related activities, and defective migration appears as an important factor. A functional AR signaling pathway delays some of these.
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http://dx.doi.org/10.18632/aging.101303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680557PMC
October 2017

The Impact of Waiting List BMI Changes on the Short-term Outcomes of Lung Transplantation.

Transplantation 2018 02;102(2):318-325

Lung Transplant Program, Centre Hospitalier de l'Université de Montréal, Québec, Canada.

Background: Obesity and underweight are associated with a higher postlung transplantation (LTx) mortality. This study aims to assess the impact of the changes in body mass index (BMI) during the waiting period for LTx on early postoperative outcomes.

Methods: Medical records of 502 consecutive cases of LTx performed at our institution between 1999 and 2015 were reviewed. Patients were stratified per change in BMI category between pre-LTx assessment (candidate BMI) and transplant BMI as follows: A-candidate BMI, less than 18.5 or 18.5 to 29.9 and transplant BMI, less than 18.5; B-candidate BMI, less than 18.5 and transplant BMI, 18.5 to 29.9; C-candidate BMI, 18.5 to 29.9 and transplant BMI, 18.5 to 29.9; D-candidate BMI, 30 or greater and transplant BMI, 18.5 to 29.9; and E-candidate BMI, 30 or greater or 18.5 to 29.9 and transplant BMI, 30 or greater. Our primary outcome was in-hospital mortality and secondary outcomes were length of mechanical ventilation, intensive care unit length of stay (LOS), hospital LOS and postoperative complications.

Results: BMI variation during the waiting time was common, as 1/3 of patients experienced a change in BMI category. Length of mechanical ventilation (21 days vs 9 days; P = 0.018), intensive care unit LOS (26 days vs 15 days; P = 0.035), and rates of surgical complications (76% vs 44%; P = 0.018) were significantly worse in patients of group E versus group D. Obese candidates who failed to decrease BMI less than 30 by transplant exhibited an increased risk of postoperative mortality (odds ratio, 2.62; 95% confidence interval, 1.01-6.48) compared with patients in group C. Pre-LTx BMI evolution had no impact on postoperative morbidity and mortality in underweight patients.

Conclusions: Our results suggest that obese candidates with an unfavorable pretransplant BMI evolution are at greater risk of worse post-LTx outcomes.
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http://dx.doi.org/10.1097/TP.0000000000001919DOI Listing
February 2018

Impaired rib bone mass and quality in end-stage cystic fibrosis patients.

Bone 2017 05 22;98:9-17. Epub 2017 Feb 22.

Department of Medicine, Centre Hospitalier de l'Université de Montréal, 1058 St-Denis Street, Montreal, Québec H2X 3J4, Canada. Electronic address:

Background: Advancements in research and clinical care have considerably extended the life expectancy of cystic fibrosis (CF) patients. However, with this extended survival come comorbidities. One of the leading co-morbidities is CF-related bone disease (CFBD), which progresses with disease severity and places patients at high risk for fractures, particularly of the ribs and vertebrae. Evidence that CF patients with vertebral fractures had higher bone mineral density (BMD) than the nonfracture group led us to postulate that bone quality is impaired in these patients. We therefore examined rib specimens resected at the time of lung transplant in CF patients to measure parameters of bone quantity and quality.

Methods: In this exploratory study, we analysed 19 end-stage CF and 13 control rib specimens resected from otherwise healthy lung donors. BMD, bone microarchitecture, static parameters of bone formation and resorption and microcrack density of rib specimens were quantified by imaging, histomorphometric and histological methods. Variables reflecting the mineralization of ribs were assessed by digitized microradiography. The degree of bone mineralization (g/cm) and the heterogeneity index of the mineralization (g/cm) were calculated for trabecular and cortical bone.

Results: Compared to controls, CF ribs exhibited lower areal and trabecular volumetric BMD, decreased trabecular thickness and osteoid parameters, and increased microcrack density, that was particularly pronounced in specimens from patients with CF-related diabetes. Static parameters of bone resorption were similar in both groups. Degree of mineralization of total bone, but not heterogeneity index, was increased in CF specimens.

Conclusion: The combination of reduced bone mass, altered microarchitecture, imbalanced bone remodeling (maintained bone resorption but decreased formation), increased microdamage and a small increase of the degree of mineralization, may lead to decreased bone strength, which, when coupled with chronic coughing and chest physical therapy, may provide an explanation for the increased incidence of rib fractures previously reported in this population.
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http://dx.doi.org/10.1016/j.bone.2017.02.007DOI Listing
May 2017

Vitamin D intervention in preschoolers with viral-induced asthma (DIVA): a pilot randomised controlled trial.

Trials 2016 07 26;17(1):353. Epub 2016 Jul 26.

Departments of Pediatrics and of Social and Preventive Medicine and Clinical Research and Knowledge Transfer Unit on Childhood Asthma, Research Centre, Sainte-Justine University Health Centre, Université de Montréal, Montreal, QC, Canada.

Background: Trials in school-aged children suggest vitamin D supplementation reduces asthma exacerbations. Primary aim: to examine whether vitamin D3 (100,000 IU) rapidly raises serum 25-hydroxyvitamin D (25OHD) ≥75 nmol/L in asthmatic preschoolers.

Methods: In a double-blind, randomised, placebo-controlled trial, preschool-aged children with asthma received 100,000 IU vitamin D3 (intervention) or placebo (control), followed by 400 IU vitamin D3 daily for 6 months. Serum 25OHD was measured at baseline, 10 days, 3 and 6 months. Outcomes included the group difference in 25OHD change from baseline at 3 months (Δ25OHD); the proportion of children with 25OHD ≥75 nmol/L at 3 months; the pattern in serum vitamin D over 6 months; the proportion of children with hypercalciuria at any time point (safety); and group rates for oral corticosteroids. Continuous outcomes were analysed using generalised linear mixed models and group rate ratios of events per child were assessed using a Poisson distribution model.

Results: Twenty-two children were randomised (intervention:11; control:11) during winter. At 3 months, the group difference in Δ25OHD (7.2 nmol/L; 95 % CI: -13.7, 28.1) was not significant; yet, 100 % versus 54.5 % (intervention versus control) had serum 25OHD ≥75 nmol/L. There was a significant group difference in Δ25OHD at 10 days (110.3 nmol/L; 95 % CI: 64.0, 156.6). One child in each group had transient hypercalciuria at 10 days. Group oral corticosteroids rates were 0.82 and 1.18/child, intervention versus control (rate ratio = 0.68; 95 % CI: 0.30, 1.62; non-significant).

Conclusions: Following 100,000 IU vitamin D3, all children reached serum 25OHD ≥75 nmol/L, compared with half who received placebo. Daily supplementation, sun exposure and insufficient power may explain the absence of a significant 3-month group difference in Δ25OHD. No clinically important alterations in bone metabolism biomarkers occurred. Group oral corticosteroid rates will inform sample size calculations for the larger trial. ( NCT01999907 , 25 November 2013).
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http://dx.doi.org/10.1186/s13063-016-1483-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4960871PMC
July 2016

Cow's Milk Allergy and Bone Mineral Density in Prepubertal Children.

Pediatrics 2016 05;137(5)

Centre Hospitalier Universitaire Sainte-Justine Research Center, Université de Montréal, Montreal, Quebec, Canada; and Allergy, Department of Pediatrics,

Background And Objectives: Recent data suggest that cow's milk allergy (CMA) has become more persistent, prolonging treatment via strict elimination of cow's milk products into a period of skeletal growth. The objectives of this study were to compare bone mineral density (BMD), vitamin D status, and dietary intakes of calcium and vitamin D between prepubertal children with persistent CMA and those with non-cow's milk food allergies (NCMA) as control subjects and to assess the use of and compliance to calcium and vitamin D supplementation among children with persistent CMA.

Methods: Fifty-two children with persistent CMA and 29 with NCMA were recruited. BMD was measured by using dual energy radiograph absorptiometry, and vitamin D status was assessed by using plasma 25-hydroxyvitamin D concentrations. Calcium and vitamin D intakes, as well as compliance to calcium and vitamin D supplementation, were recorded.

Results: Lumbar spine BMD z scores were significantly lower in children with CMA. Low bone mass was detected in 6% of the CMA group compared with none in the NCMA group. Children with CMA displayed significantly lower calcium intakes than control subjects. Vitamin D status was not reduced in children with CMA compared with control subjects. Fewer than one-half of children with CMA reported the use of calcium and vitamin D supplements. However, adherence was high among supplement users, with a mean compliance rate of 5.5 days per week.

Conclusions: These prepubertal children with persistent CMA had lower lumbar spine BMD z scores than children with NCMA, which likely resulted from lower calcium intake.
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http://dx.doi.org/10.1542/peds.2015-1742DOI Listing
May 2016

Vitamin D attenuates inflammation in CFTR knockdown intestinal epithelial cells but has no effect in cells with intact CFTR.

Am J Physiol Gastrointest Liver Physiol 2016 04 18;310(8):G539-49. Epub 2016 Feb 18.

Research Centre, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada; and Department of Nutrition, Université de Montréal, Montréal, Quebec, Canada

The cystic fibrosis (CF) intestine is characterized by chronic inflammation. CF patients are instructed to ingest supplemental vitamin D on a daily basis thereby exposing their intestinal tract to pharmacological amounts of this vitamin. It has been shown that vitamin D exerts intestinal anti-inflammatory properties. We therefore postulate that vitamin D may be beneficial in the management of CF intestinal inflammation by attenuating cellular inflammatory responses. In this study, we investigated the anti-inflammatory effects of the oral form of vitamin D3 (cholecalciferol) and its metabolites, 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3, on cytokine-induced inflammatory responses in intestinal epithelial Caco-2/15 cells with intact expression of CF transmembrane conductance regulator (CFTR) and knockdown for CFTR. We show that 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 inhibited p38MAPK phosphorylation and that these effects were not mediated by changes in the expression of MAPK phosphatase-1 (MKP-1). However, 1,25-dihydroxyvitamin D3 exhibited superior anti-inflammatory effects as it furthermore reduced cytokine-induced NF-κB nuclear translocation and interleukin-8 mRNA stability and secretion. Intriguingly, the anti-inflammatory effects of vitamin D metabolites were only observed in CFTR knockdown cells, which may be explained by alterations in its catabolism associated with changes in CYP24A1 expression. These observations were supported in vivo whereby Cftr(-/-) mice fed large amounts of vitamin D3 for 2 mo led to a reduction in the number of eosinophils and apoptotic cells in the duodenal mucosa of females but not males. Altogether, these findings suggest that vitamin D exerts intestinal anti-inflammatory actions under specific circumstances and may thus prove beneficial in CF.
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http://dx.doi.org/10.1152/ajpgi.00060.2015DOI Listing
April 2016

CFTR silencing in pancreatic β-cells reveals a functional impact on glucose-stimulated insulin secretion and oxidative stress response.

Am J Physiol Endocrinol Metab 2016 Feb 1;310(3):E200-12. Epub 2015 Dec 1.

Research Centre, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada; Department of Nutrition, Université de Montréal, Montreal, Quebec, Canada;

Cystic fibrosis (CF)-related diabetes (CFRD) has become a critical complication that seriously affects the clinical outcomes of CF patients. Although CFRD has emerged as the most common nonpulmonary complication of CF, little is known about its etiopathogenesis. Additionally, whether oxidative stress (OxS), a common feature of CF and diabetes, influences CFRD pathophysiology requires clarification. The main objective of this study was to shed light on the role of the cystic fibrosis transmembrane conductance regulator (CFTR) in combination with OxS in insulin secretion from pancreatic β-cells. CFTR silencing was accomplished in MIN6 cells by stable expression of small hairpin RNAs (shRNA), and glucose-induced insulin secretion was evaluated in the presence and absence of the valuable prooxidant system iron/ascorbate (Fe/Asc; 0.075/0.75 mM) along with or without the antioxidant Trolox (1 mM). Insulin output from CFTR-silenced MIN6 cells was significantly reduced (∼ 70%) at basal and at different glucose concentrations compared with control Mock cells. Furthermore, CFTR silencing rendered MIN6 cells more sensitive to OxS as evidenced by both increased lipid peroxides and weakened antioxidant defense, especially following incubation with Fe/Asc. The decreased insulin secretion in CFTR-silenced MIN6 cells was associated with high levels of NF-κB (the major participant in inflammatory responses), raised apoptosis, and diminished ATP production in response to the Fe/Asc challenge. However, these defects were alleviated by the addition of Trolox, thereby pointing out the role of OxS in aggravating the effects of CFTR deficiency. Our findings indicate that CFTR deficiency in combination with OxS may contribute to endocrine cell dysfunction and insulin secretion, which at least in part may explain the development of CFRD.
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http://dx.doi.org/10.1152/ajpendo.00333.2015DOI Listing
February 2016

CFTR Knockdown induces proinflammatory changes in intestinal epithelial cells.

J Inflamm (Lond) 2015 7;12:62. Epub 2015 Nov 7.

Research Centre, CHU Sainte-Justine, 3175 Cote Sainte-Catherine Rd, Montreal, Quebec H3T 1C5 Canada ; Department of Nutrition, Université de Montreal, 2405 Cote Sainte-Catherine Rd, Montreal, Quebec H3T 1A8 Canada.

Background: Hyperinflammation is a hallmark feature of cystic fibrosis (CF) airways. However, inflammation has also been documented systemically and, more recently, in extrapulmonary CF-affected tissues such as the pancreas and intestine. The pathogenesis of CF-related inflammation and more specifically the role of the cystic fibrosis transmembrane conductance regulator (CFTR) in that respect are not entirely understood. We have tested the hypothesis that genetic depletion of CFTR will affect the inflammatory status of human intestinal epithelial cell lines.

Methods: CFTR expression was genetically depleted from Caco-2/15 and HT-29 cells using short hairpin RNA interference (shRNAi). Inflammatory conditions were induced by the addition of human recombinant tumor necrosis factor (TNF) or Interleukin-1β (IL-1β) for various periods of time. Gene expression, mRNA stability and secreted levels of interleukin (IL)-6, -8 and 10 were assessed. Analysis of pro- and anti-inflammatory signaling pathways including mitogen-activated protein kinases (p38, ERK 1/2 and JNK), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα), and nuclear factor-kappa B (NF-κB) was also performed. Eosinophils were counted in the jejunal mucosa of Cftr-/- and Cftr+/+ mice.

Results: CFTR gene and protein knockdown caused a significant increase in basal secretion of IL-8 as well as in IL-1β-induced secretion of IL-6 and -8. Release of the anti-inflammatory cytokine, IL-10, remained unaffected by CFTR depletion. The enhanced secretion of IL-8 stems in part from increased IL8 mRNA levels and greater activation of ERK1/2 MAPK, IκBα and NF-κB in the CFTR knockdown cells. By contrast, phosphorylation levels of p38 and JNK MAPK did not differ between control and knockdown cells. We also found a higher number of infiltrating eosinophils in the jejunal mucosa of Cftr -/- females, but not males, compared to Cftr +/+ mice, thus providing in vivo support to our in vitro findings.

Conclusion: Collectively, these data underscore the role played by CFTR in regulating the intestinal inflammatory responses. Such findings lend support to the theory that CFTR exerts functions that may go beyond its role as a chloride channel whereby its disruption may prevent cells to optimally respond to exogenous or endogenous challenges. These observations are of particular interest to CF patients who were found to display alterations in their intestinal microbiota, thus predisposing them to pathogens that may elicit exaggerated inflammatory responses.
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http://dx.doi.org/10.1186/s12950-015-0107-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636765PMC
November 2015

Impact of sex on insulin secretion in cystic fibrosis.

J Clin Endocrinol Metab 2014 May 21;99(5):1767-73. Epub 2014 Jan 21.

Platform for Research on Obesity, Metabolism, and Diabetes (A.C., L.B., S.Z., E.H., M.-S.G., L.C., Y.B., R.R.-L.), Metabolic Unit laboratory, Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada H2W 1R7; Department of Nutrition (A.C., L.B., S.Z., E.H., M.-S.G., G.M., R.R.-L.), Université de Montréal, Montréal, Québec, Canada H3T 1A8; Endocrinology Division (R.R.-L.), Department of Medicine, Université de Montréal, Montréal, Québec, Canada H3T1J4; Department of Medicine (L.C., Y.B., R.R.-L.), Université de Montréal, Montréal, Québec, Canada H3T1J4; Research Center (G.M.), Centre Hospitalier de l'Université Sainte-Justine, Université de Montréal, Montréal, Québec, Canada H3T 1C5; and Cystic Fibrosis Clinic (Y.B., R.R.-L.) of the Centre hospitalier de l'Université de Montréal, Montréal, Québec, Canada H2W1T8; and Montreal Diabetes Research Center (R.R.-L.), Montréal, Québec, Canada H1W4A4.

Context: Cystic fibrosis-related diabetes is primarily due to a defect in insulin secretion. Women with cystic fibrosis (CF) are at higher risk of developing CF-related diabetes.

Objective: The objective of the study was to examine sex differences in insulin and glucose homeostasis. We hypothesized that in CF, women would display lower insulin secretion than men.

Design: This was a study based on an ongoing observational CF cohort with a mean follow-up of 19.9 ± 5.2 months.

Setting: The study was conducted at the CF clinic of the Centre Hospitalier de l'Université de Montréal (Québec, Canada).

Patients: From 230 adults with CF (123 men, 107 women) of similar age and functional pulmonary status, 104 retested after the follow-up. Age-matched healthy individuals (25 men, 19 women) were included in the study.

Interventions: Participants underwent a 2-hour oral glucose tolerance test with 30-minute interval sample measurements.

Main Outcome Measure: Plasma insulin and glucose levels were measured.

Results: Women with CF had higher overall insulin secretion as compared with men with CF (P ≤ .05) but similar to healthy women (P = .606). Men with CF had lower overall insulin secretion than healthy men (P = .020) and higher insulin sensitivity (P = .009) than women with CF. PATIENTS with CF displayed higher overall glucose excursions than healthy patients. Sex-related differences were still observed in the CF cohort after follow-up.

Conclusions: Surprisingly, in CF, adult women presented higher insulin secretion than adult men at a comparable level with what is observed in healthy individuals. Potential implications of this sex dimorphism in CF remain to be established.
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http://dx.doi.org/10.1210/jc.2013-2756DOI Listing
May 2014

Plasma zinc in adults with cystic fibrosis: correlations with clinical outcomes.

J Trace Elem Med Biol 2014 Jan 6;28(1):60-4. Epub 2013 Nov 6.

Department of Nutrition, University of Montreal, Montreal, Quebec, Canada H3C 3J7; Gastroenterology, Hepatology and Nutrition Unit, CHU Sainte-Justine Research Center, Montréal, Québec, Canada H3T 1C5. Electronic address:

Background: Zinc status has been previously documented in cystic fibrosis (CF) infants, children and adolescents. However, despite the increasing life expectancy observed in CF populations, data regarding zinc status of CF adults are surprisingly lacking. The objectives of this study were to (1) characterize zinc status and (2) explore associations between zinc status and clinical outcomes of CF adult patients.

Methods: A retrospective chart review was performed for patients who had their plasma zinc measured between 2009 and 2012. Data included demographics, clinical characteristics, biochemical parameters and co-morbid conditions.

Results: A total of 304 CF patients were included in the study. These patients displayed a good nutritional status (mean BMI±SD: 22.7±3.5) and moderate lung disease (mean FEV1±SD: 66.3±22.2). Low plasma zinc concentration (<9.2μmol/L) was found in 68 out of 304 CF patients (22.4%). Compared to patients with normal zinc, those with low zinc had significantly lower forced vital capacity and forced expiratory volume in one second. 72% of CF adults with low zinc suffered from bone disease (vs 49% with normal zinc, p=0.037) and 79% had impaired glycemic status (vs 58%, p=0.016). Accordingly, negative correlations were found between plasma zinc and glucose (r=-0.139, p=0.0001), HbA1c (r=-0.237, p=0.0001) and fructosamine (r=-0.134, p=0.034). In multiple linear regression, albumin and glycemic status were significant predictors of plasma zinc.

Conclusion: Our data indicated that nearly one quarter of CF adults with good nutritional status and moderate lung disease had low plasma zinc concentration and that low zinc status was associated with worse clinical outcomes.
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http://dx.doi.org/10.1016/j.jtemb.2013.10.003DOI Listing
January 2014

Role of the apical and basolateral domains of the enterocyte in the regulation of cholesterol transport by a high glucose concentration.

Biochem Cell Biol 2013 Dec 26;91(6):476-86. Epub 2013 Jul 26.

a Research Centre, CHU Ste-Justine, 3175 Ste-Catherine Road, Montreal, QC H3T 1C5, Canada.

We have recently shown that a high glucose (HG) concentration raised intestinal cholesterol (CHOL) transport and metabolism in intestinal epithelial cells. The objective of the present work is to determine whether the stimulus for increased CHOL absorption by glucose originates from the apical site (corresponding to the intestinal lumen) or from the basolateral site (related to blood circulation). We tackled this issue by using differentiated Caco-2/15 cells. Only basolateral medium, supplemented with 25 mmol/L glucose, stimulated [(14)C]-CHOL uptake via the up-regulation of the critical CHOL transporter NPC1L1 protein, as confirmed by its specific ezetimibe inhibitor that abolished the rise in glucose-mediated CHOL capture. No significant changes were noted in SR-BI and CD36. Elevated CHOL uptake was associated with an increase in the transcription factors SREBP-2, LXR-β, and ChREBP, along with a fall in RXR-α. Interestingly, although the HG concentration in the apical medium caused modest changes in CHOL processing, its impact was synergetic with that of the basolateral medium. Our results suggest that HG concentration influences positively intestinal CHOL uptake when present in the basolateral medium. In addition, excessive consumption of diets containing high levels of carbohydrates may strengthen intestinal CHOL uptake in metabolic syndrome, thereby contributing to elevated levels of circulating CHOL and, consequently, the risk of developing type 2 diabetes and cardiovascular disease.
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http://dx.doi.org/10.1139/bcb-2013-0053DOI Listing
December 2013

Vitamin D bioavailability in cystic fibrosis: a cause for concern?

Nutr Rev 2012 May 30;70(5):280-93. Epub 2012 Mar 30.

Research Centre, CHU Sainte-Justine, Department of Nutrition, Université de Montréal, Montréal, Canada.

Despite the inclusion of extra vitamin D in their regimen of fat-soluble vitamin supplementation, cystic fibrosis patients remain chronically depleted of vitamin D. The persistence of suboptimal vitamin D status is often blamed on the maldigestion and malabsorption of fat. However, the mitigated success of recent clinical trials with high-dose vitamin D supplementation suggests that vitamin D bioavailability might be impaired in these patients. Given the growing understanding of the importance of this vitamin in the regulation of multiple biological functions beyond skeletal health, the present review analyzes the current literature by addressing each step of vitamin D metabolism and action in the context of this life-limiting pathology. In addition, it highlights the importance of vitamin D in relation to organs and or conditions affected by cystic fibrosis.
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http://dx.doi.org/10.1111/j.1753-4887.2012.00471.xDOI Listing
May 2012

Oxidative stress and mitochondrial functions in the intestinal Caco-2/15 cell line.

PLoS One 2010 Jul 27;5(7):e11817. Epub 2010 Jul 27.

Department of Nutrition, Research Center, CHU-Sainte-Justine, Université de Montréal, Montreal, Canada.

Background: Although mitochondrial dysfunction and oxidative stress are central mechanisms in various pathological conditions, they have not been extensively studied in the gastrointestinal tract, which is known to be constantly exposed to luminal oxidants from ingested foods. Key among these is the simultaneous consumption of iron salts and ascorbic acid, which can cause oxidative damage to biomolecules.

Methodology/principal Findings: The objective of the present work was to evaluate how iron-ascorbate (FE/ASC)-mediated lipid peroxidation affects mitochondrion functioning in Caco-2/15 cells. Our results show that treatment of Caco-2/15 cells with FE/ASC (0.2 mM/2 mM) (1) increased malondialdehyde levels assessed by HPLC; (2) reduced ATP production noted by luminescence assay; (3) provoked dysregulation of mitochondrial calcium homeostasis as evidenced by confocal fluorescence microscopy; (4) upregulated the protein expression of cytochrome C and apoptotic inducing factor, indicating exaggerated apoptosis; (5) affected mitochondrial respiratory chain complexes I, II, III and IV; (6) elicited mtDNA lesions as illustrated by the raised levels of 8-OHdG; (7) lowered DNA glycosylase, one of the first lines of defense against 8-OHdG mutagenicity; and (8) altered the gene expression and protein mass of mitochondrial transcription factors (mtTFA, mtTFB1, mtTFB2) without any effects on RNA Polymerase. The presence of the powerful antioxidant BHT (50 microM) prevented the occurrence of oxidative stress and most of the mitochondrial abnormalities.

Conclusions/significance: Collectively, our findings indicate that acute exposure of Caco-2/15 cells to FE/ASC-catalyzed peroxidation produces harmful effects on mitochondrial functions and DNA integrity, which are abrogated by the powerful exogenous BHT antioxidant. Functional derangements of mitochondria may have implications in oxidative stress-related disorders such as inflammatory bowel diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0011817PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2910735PMC
July 2010

CFTR depletion results in changes in fatty acid composition and promotes lipogenesis in intestinal Caco 2/15 cells.

PLoS One 2010 May 5;5(5):e10446. Epub 2010 May 5.

Research Centre, CHU Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada.

Background: Abnormal fatty acid composition (FA) in plasma and tissue lipids frequently occurs in homozygous and even in heterozygous carriers of cystic fibrosis transmembrane conductance regulator (CFTR) mutations. The mechanism(s) underlying these abnormalities remained, however, poorly understood despite the potentially CFTR contributing role.

Methodology/principal Findings: The aim of the present study was to investigate the impact of CFTR depletion on FA uptake, composition and metabolism using the intestinal Caco-2/15 cell line. shRNA-mediated cftr gene silencing induced qualitative and quantitative modifications in FA composition in differentiated enterocytes as determined by gas-liquid chromatography. With the cftr gene disruption, there was a 1,5 fold increase in the total FA amount, largely attributable to monounsaturated and saturated FA compared to controls. The activity of delta-7 desaturase, estimated by the 16:1(n-7)/16:0, was significantly higher in knockdown cells and consistent with the striking elevation of the n-7 FA family. When incubated with [14C]-oleic acid, CFTR-depleted cells were capable of quick incorporation and export to the medium concomitantly with the high protein expression of L-FABP known to promote intracellular FA trafficking. Accordingly, lipoprotein vehicles (CM, VLDL, LDL and HDL), isolated from CFTR knockdown cells, exhibited higher levels of radiolabeled FA. Moreover, in the presence of [14C]-acetate, knockdown cells exhibited enhanced secretion of newly synthesized phospholipids, triglycerides, cholesteryl esters and free FA, thereby suggesting a stimulation of the lipogenic pathway. Conformably, gene expression of SREBP-1c, a key lipogenic transcription factor, was increased while protein expression of the phosphorylated and inactive form of acetylCoA carboxylase was reduced, confirming lipogenesis induction. Finally, CFTR-depleted cells exhibited lower gene expression of transcription factors (PPARalpha, LXRalpha, LXRbeta and RXRalpha).

Conclusions/significance: Collectively, our results indicate that CFTR depletion may disrupt FA homeostasis in intestinal cells through alterations in FA uptake and transport combined with stimulation of lipogenesis that occurs by an LXR/RXR-independent mechanism. These findings exclude a contributing role of CFTR in CF-associated fat malabsorption.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0010446PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2864762PMC
May 2010
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