Some Encouraging References and Abstracts Compiled by SOTO-USA for Aid and Suggestions to CF Patients and Families
Cotellessa_M; Minicucci_L; Lorini_R "When should hyperglycemia be treated in
cystic fibrosis? [letter]" J Pediatr, 2000 05, 136: 5, 706-7
Lees_CM; Smyth_RL The current management of cystic fibrosis. Int J Clin
Pract, 2000 04, 54: 3, 171-9
Abstract
Cystic fibrosis (CF) is one of the commonest lethal inherited conditions
among Caucasians. It affects multiple organ systems and exhibits a range of
clinical problems of varying severity. Life expectancy has improved in recent
years as treatment regimes have become more intensive, but current treatments
are expensive, often time consuming and may affect quality of life. This
review summarises the treatments currently used in the management of patients
with CF, and the evidence for these.
Cobos_N; DanŽs_I; Gartner_S; Gonz‡lez_M; Li–‡n_S; Arnau_JM
"DNase use in the daily care of cystic fibrosis: who benefits from it and to
what extent? Results of a cohort study of 199 patients in 13 centres. DNase
National Study Group." Eur J Pediatr, 2000 03, 159: 3, 176-81
Abstract
Short-term clinical trials with DNase have shown minor to moderate benefits
in cystic fibrosis patients. This study was performed to analyse the
effectiveness of DNase use in daily practice and to obtain information on its
effects in the long term and at different disease stages. Patients being
treated in 13 specialised units were included if they started DNase treatment
before June 1996. Baseline data before DNase use and data during the DNase
treatment period were recorded. Of the 199 patients included in the study 166
continued on DNase treatment while the data were being collected. The mean
age (95% CI) was 14.5 (13.7; 15,2) years; 103 (51.8%) patients were female.
The mean maximum change in forced expiratory volume in 1 s (FEV(1)) was
observed during the first month of treatment [11.1% (6.1; 16.1)]. By the end
of the first and the second year of treatment mean changes in FEV(1) were
3.3% (-1.1; 7. 6) and 5.1% (-0.7; 10.9) respectively; at the end of the same
periods 34% of patients had improved their baseline FEV(1) by 10% or more but
in around 50% of patients the level fell below the baseline. A large
inter-individual variability in changes in pulmonary function after the start
of DNase treatment was documented. In addition, the medium-term response to
treatment was correlated with early response during the first 3 months. No
consistent changes in exacerbation pattern were found during the first year
of treatment. CONCLUSIONS: The benefits of DNase use in daily practice are
limited but apparently can be maintained in the medium term in some patients.
A large inter-individual variability in response to DNase treatment has been
documented and the benefits are doubtful in around 50% of patients. This
observation points to the need to set up a withdrawal trial in these
patients, using as an eligibility criterion the early response observed
during the first 3 months of treatment.
Schneiderman_Walker_J; Pollock_SL; Corey_M; Wilkes_DD; Canny_GJ; Pedder_L;
Reisman_JJ, "A randomized controlled trial of a 3-year home exercise program
in cystic fibrosis" J Pediatr, 2000 03, 136: 3, 304-10
Abstract
OBJECTIVES: To evaluate the effects of a 3-year home exercise program on
pulmonary function and exercise tolerance in mildly to moderately impaired
patients with cystic fibrosis (CF) and to assess whether regular aerobic
exercise is a realistic treatment option. STUDY DESIGN: Seventy-two patients
with CF (7-19 years) were randomly assigned to an exercise group (a minimum
of 20 minutes of aerobic exercise, at a heart rate of approximately 150
beats/min, 3 times weekly) or a control group (usual physical activity
participation). Pulmonary function, exercise tolerance, clinical status,
hospitalizations, and compliance with therapy were monitored during scheduled
visits to the hospital's CF clinic. RESULTS: Sixty-five patients were
included in the analyses. The control group demonstrated a greater annual
decline in percent of predicted forced vital capacity compared with the
exercise group (mean slope +/- SD, -2.42 +/- 4.15 vs -0.25 +/- 2.81; P =.02),
with a similar trend for forced expiratory volume in 1 second (-3.47 +/- 4.93
vs -1.46 +/- 3. 55; P =.07). Patients remained compliant with the exercise
program over the study period. An improved sense of well-being was reported
with exercise. CONCLUSIONS: Pulmonary function declined more slowly in the
exercise group than in the control group, suggesting a benefit for patients
with CF participating in regular aerobic exercise. Consistent compliance with
the home exercise program and a self-reported positive attitude toward
exercise provide further evidence of the feasibility and value of including
an aerobic exercise program in the conventional treatment regimen of patients
with CF.
Drapkin_PT; ORiordan_CR; Yi_SM; Chiorini_JA; Cardella_J; Zabner_J; Welsh_MJ
, "Targeting the urokinase plasminogen activator receptor enhances gene
transfer to human airway epithelia." J Clin Invest, 2000 03, 105: 5, 589-96
Abstract
Developing gene therapy for cystic fibrosis has been hindered by limited
binding and endocytosis of vectors by human airway epithelia. Here we show
that the apical membrane of airway epithelia express the urokinase
plasminogen activator receptor (uPAR). Urokinase plasminogen activator (uPA),
or a 7-residue peptide derived from this protein (u7-peptide), bound the
receptor and stimulated apical endocytosis. Both ligands enhanced gene
transfer by nonspecifically bound adenovirus and adeno-associated virus
vectors and by a modified adenovirus vector that had been coupled to the
u7-peptide. These data provide the first evidence that targeting an apical
receptor can circumvent the two most important barriers to gene transfer in
airway epithelia. Thus, the uPA/uPAR system may offer significant advantages
for delivering genes and other pharmaceuticals to airway epithelia.
Bar_Or_O "Home-based exercise programs in cystic fibrosis: are they worth
it? [editorial; comment]" J Pediatr, 2000 03, 136: 3, 279-80
Hunter_I; Stewart_L; Mukhopadhyay_S, "Fat absorption in cystic fibrosis
after correction of hypokalaemia [letter]" Lancet, 2000 00, 355: 9207, 900
Abstract
Extracellular potassium up-regulates exocrine pancreatic function in tissue
preparations of mammalian pancreatic lobules. We report on a child with
cystic fibrosis in whom clinical evidence suggested that this laboratory
observation may be of relevance to clinical practice.
Cafferata_EG; Gonz‡lez_Guerrico_AM; Giordano_L; Pivetta_OH;
"Interleukin-1beta regulates CFTR expression in human intestinal T84 cells.
Biochim Biophys Acta, 2000 00, 1500: 2, 241-8
Abstract
Cystic fibrosis is an autosomal recessive genetic disease, produced by a
mutation in the CFTR gene that impairs its function as a chloride channel. In
this work, we have examined the effects of interleukin-1beta (IL-1beta) on th
e expression of CFTR in human colonic T84 cells. Treatment of T84 cells with
IL-1beta (0.25 ng/ml) for 4 h resulted in an increased CFTR expression (mRNA
and protein). However, higher doses of IL-1beta (1 ng/ml and over) produced
inhibition of CFTR mRNA and protein expression. The protein kinase C (PKC)
inhibitors H7 (50 microM) and GF109203X (1 microM) inhibited the stimulatory
effect of IL-1beta. Similar effects were seen in the presence of the protein
tyrosine kinase (PTK) inhibitors genistein (60 microM) and herbymicin A (2
microM). These results suggest that some PKC isoform(s) and at least a PTK
might be involved in the CFTR up-regulation induced by IL-1beta. The
repression of CFTR up-regulation by cycloheximide (35.5 microM) suggests the
participation of a de novo synthesized protein. Results obtained by using the
RNA polymerase II inhibitor DRB (78 microM), suggest that the increased mRNA
levels seen after IL-1beta treatment are not due to an increased stability of
the message. We conclude that the CFTR mRNA and protein levels are modulated
by IL-1beta, this cytokine being the first extracellular protein known to
up-regulate CFTR gene expression.
Wallace_DP; Tomich_JM; Eppler_JW; Iwamoto_T; Grantham_JJ; Sullivan_LP "A
synthetic channel-forming peptide induces Cl(-) secretion: modulation by
Ca(2+)-dependent K(+) channels." Biochim Biophys Acta, 2000 00, 1464: 1,
69-82
Abstract
A synthetic Cl(-) channel-forming peptide, C-K4-M2GlyR, applied to the apical
membrane of human epithelial cell monolayers induces transepithelial Cl(-)
and fluid secretion. The sequence of the core peptide, M2GlyR, corresponds to
the second membrane-spanning region of the glycine receptor, a domain thought
to line the pore of the ligand-gated Cl(-) channel. Using a pharmacological
approach, we show that the flux of Cl(-) through the artificial Cl(-) channel
can be regulated by modulating basolateral K(+) efflux through
Ca(2+)-dependent K(+) channels. Application of C-K4-M2GlyR to the apical
surface of monolayers composed of human colonic cells of the T84 cell line
generated a sustained increase in short-circuit current (I(SC)) and caused
net fluid secretion. The current was inhibited by the application of
clotrimazole, a non-specific inhibitor of K(+) channels, and charybdotoxin, a
potent inhibitor of Ca(2+)-dependent K(+) channels. Direct activation of
these channels with 1-ethyl-2-benzimidazolinone (1-EBIO) greatly amplified
the Cl(-) secretory current induced by C-K4-M2GlyR. The effect of the
combination of C-K4-M2GlyR and 1-EBIO on I(SC) was significantly greater than
the sum of the individual effects of the two compounds and was independent of
cAMP. Treatment with 1-EBIO also increased the magnitude of fluid secretion
induced by the peptide. The cooperative action of C-K4-M2GlyR and 1-EBIO on
I(SC) was attenuated by Cl(-) transport inhibitors, by removing Cl(-) from
the bathing solution and by basolateral treatment with K(+) channel blockers.
These results indicate that apical membrane insertion of Cl(-)
channel-forming peptides such as C-K4-M2GlyR and direct activation of
basolateral K(+) channels with benzimidazolones may coordinate the apical
Cl(-) conductance and the basolateral K(+) conductance, thereby providing a
pharmacological approach to modulating Cl(-) and fluid secretion by human
epithelia deficient in cystic fibrosis transmembrane conductance regulator
Cl(-) channels.
ANTHONY, H; CATTO-SMITH, A; PAXTON, S; PHELAN, P; Physiological and
Psychosocial Contributors to Malnutrition in Children with Cystic Fibrosis:
Review CLINICAL NUTRITION. 1999 DEC;18(6): 327-35
ABSTRACT: Malnutrition was once thought to be an inevitable consequence of
cystic fibrosis (CF). It is now considered preventable but still contributes
considerable morbidity in children. Malnutrition is linked to poorer
pulmonary function, reduced survival and quality of life. As the anticipated
lifespan of children with CF continues to lengthen, the prevention of
malnutrition attains greater importance. This review explores the complex
organic and psychosocial factors implicated in the aetiology of malnutrition
associated with CF.
ATEGBO, S; DABADIE, A; DRUON, D; GOTTRAND, F; HANKARD, R; MICHAUD, L; TURCK,
D; Effect of Glucose to Fat Ratio on Energy Substrate Disposal in Children
with Cystic Fibrosis Fed Enterally CLINICAL NUTRITION. 1999 OCT:
18(5):297-300
ABSTRACT: High fat containing diets lower VCO2 in patients with impaired
pulmonary function fed at a high level of energy intake. We tested the effect
of a high fat enteral nutrition on VCO2 and substrate oxidation in cystic
fibrosis patients fed enterally 130% RDA. VCO2 and substrate oxidation were
studied in a group of eight 6-19 year old patients while receiving for 1
month and in a random order isocaloric (1000 kcal/m2), isonitrogenous enteral
diet with a normal fat and a high fat content (40% and 67% of non-protein
energy intake). Substrate oxidation and net balance were estimated using
indirect calorimetry at the end of each study period. Overnight high fat
enteral infusion resulted in no significant change in VCO2 and VO2 but
lowered RQ and non-protein RQ. In spite of a higher glucose oxidation rate,
glucose net balance was significantly higher during normal fat formula
administration. The present study failed to show any benefit of a high fat
diet on VCO2 in non-oxygenodependant cystic fibrosis children and adolescents
fed slightly above RAD. Normal fat enteral formula led to higher glycogen
repletion.
BOAS, SR; DANDURAN, MJ; MCCOLLEY, SA; Energy Metabolism During Anaerobic
Exercise in Children with Cystic Fibrosis and Asthma MEDICINE AND SCIENCE
IN SPORTS AND EXERCISE. 1999 SEP ;31(9):1242-9
ABSTRACT: Purpose: The nature of a child's daily physical activity requires
both aerobic and anaerobic energy metabolism. Aerobic exercise becomes
compromised with advancing airway obstruction in children with cystic
fibrosis (CF) and asthma (AS). Whether children with CF will have altered
metabolic responses to supramaximal exercise when compared with asthmatics or
healthy controls is still undertermined. Methods: Twenty-five children with
CF, 22 with AS, and 23 healthy controls (CN) performed an incremental graded
aerobic and Wingate anaerobic test (WAnT) on a cycle ergometer. Analysis of
gas exchange and ventilatory data was collected and averaged every 5 s to
estimate ventilatory kinetics and energy system contributions during both
tests. Results: The CF and AS groups had mild lower airway obstruction (FEF
25-75% less than 80%) as compared with the CN. All three groups demonstrated
similar anaerobic (mean and peak power during the WAnT) and aerobic exercise
performance (peak oxygen consumption). In contrast to the AS or CN groups,
children with CF used a lower percentage of their peak VO2 and VE during each
phase of the WAnT, suggesting a preferential use of ATP/phosphocreatine and
glycolytic energy stores compared with aerobic pathways. Greater reliance on
anaerobic pathways during the WAnT in children with CF could be due to the
physiologic sequelae underlying chronic obstructive lung disease. Conclusion:
Oxygen uptake kinetics appeared similar for all three groups. Although the
energy needed to perform the WAnT can be met by subjects with CF,
abnormalities in energy metabolism may exist for this group during exercise.
LUDER, E; Gene Therapy for Cystic Fibrosis TOPICS IN CLINICAL
NUTRITION. 1999 SEP ;14(4):22-30
ABSTRACT: Cystic fibrosis (CF) is a common genetic disorder in the Caucasian
population. The gen was identified in 1989 on chromosome 7. The encoded gene
product, named cystic fibrosis transmembrane conductance regulator (CFTR),
corresponds to a cyclic adenosine monophosphate (cAMP)-regulated chloride
channel found almost exclusively in the secretory epithelial cells. Although
the major mutation that results in a single amino acid deletion (AF508)
accounts for 70% of the disease alleles, more than 700 additional mutant
alleles of different forms have been detected. A good correlation has been
found between CFTR genotype and one of the clinical variables-pancreatic
function status. Much has been learned about the feasibility of gene therapy;
however, there are substantial challenges ahead before gene therapy for CF
can be considered a proven therapeutic option.
BAR-OR, O; KRIEMLER, S; SCHURER, W; WILK, B; WILSON, WM; Preventing
Dehydration in Children With Cystic Fibrosis Who Exercise in the Heat
MEDICINE AND SCIENCE IN SPORTS AND EXERCISE. 1999 JUN;31(6):774-9
ABSTRACT: Purpose: In healthy children who exercise in the heat, the addition
of flavor, carbohydrate, and 18 mmol*L NaCl to water induced a major increase
in voluntary drink intake compared with the intake of unflavored water. This
increase was sufficient to prevent voluntary dehydration. We hypothesized
that, to achieve a similar effect in children with cystic fibrosis, whose
NaCl losses in sweat are markedly excessive, the drink should include an NaCl
concentration higher than 18 mmol*L. Methods: Eleven sub
Cystic Fibrosis Information