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Fibrosis is the end point of most renal diseases, and several glycosaminoglycans have been shown to attenuate this process. Marine invertebrate glycosaminoglycans with unique structures have opened the possibility to test these new compounds on renal fibrosis. The effect of a fucosylated chondroitin sulfate from an echinoderm marine species is reported with the use of a model of renal fibrosis in rats, termed unilateral ureteral obstruction. Animals were given 4 mg/kg body wt of fucosylated chondroitin sulfate intraperitoneally, once a day. After 14 days, their kidneys were examined by histological, immunohistochemical, and biochemical methods. Compared with control mice, collagen deposition decreased in the course of renal fibrosis in the animals receiving fucosylated chondroitin sulfate, as revealed by Sirius red staining and hydroxyproline content. The cellularity related to myofibroblasts and macrophages was also reduced, as was the production of transforming growth factor (TGF)-[beta]. The glycosaminoglycan content increased in the renal interstitium of animals submitted to unilateral ureteral obstruction compared with the control contralateral kidney, mostly due to an increase of chondroitin sulfate content. Interestingly, no change in the pattern of glycosaminoglycan deposition was observed after administration of fucosylated chondroitin sulfate. Fibrosis induced by unilateral ureteral obstruction is attenuated in P-selectin-deficient mice, which also do not respond to the invertebrate glycosaminoglycan. In conclusion, fucosylated chondroitin sulfate attenuates renal fibrosis on a ureteral obstruction model in mice preponderantly through a P-selectin-mediated mechanism. glycosaminoglycans; inflammatory cells; anti-selectin activity; cytokine expression; collagen accumulation doi: 10.1152/ajprenal.00217.2010

The prevalence and occurrence of infection with transmissible strains of Pseudomonas aeruginosa in adults with cystic fibrosis are analyzed. The infection is shown to highly correlated with a higher risk of death or lung transplantation.

Erythrocytes release ATP in response to exposure to the physiological stimulus of lowered oxygen ([O.sub.2]) tension as well as pharmacological activation of the prostacyclin receptor (IPR). ATP release in response to these stimuli requires activation of adenylyl cyclase, accumulation of cAMP, and activation of protein kinase A. The mechanism by which ATP, a highly charged anion, exits the erythrocyte in response to lowered [O.sub.2] tension or receptor-mediated IPR activation by iloprost is unknown. It was demonstrated previously that inhibiting pannexin 1 with carbenoxolone inhibits hypotonically induced ATP release from human erythrocytes. Here we demonstrate that three structurally dissimilar compounds known to inhibit pannexin 1 prevent ATP release in response to lowered [O.sub.2] tension but not to iloprost-induced ATP release. These results suggest that pannexin 1 is the conduit for ATP release from erythrocytes in response to lowered [O.sub.2] tension. However, the identity of the conduit for iloprost-induced ATP release remains unknown. iloprost; carbenoxolone; probenecid; red blood cell; cystic fibrosis transmembrane conductance regulator doi: 10.1152/ajpheart.00301.2010.

The impact of small anions on the physical properties of gel-forming mucin has been almost overlooked relative to that of cations. Recently, based on the coincident abnormalities in HC[O.sub.3.sup.-] secretion and abnormal mucus formed in the hereditary disease cystic fibrosis (CF), HC[O.sub.3.sup.-] was hypothesized to be critical in the formation of normal mucus by virtue of its ability to sequester [Ca.sup.2+] from condensed mucins being discharged from cells. However, direct evidence of the impact of HC[O.sub.3.sup.-] on mucus properties is lacking. Herein, we demonstrate for the first time that mucin diffusivity (~1/viscosity) increases as a function of [HC[O.sub.3.sup.-]]. Direct measurements of exocytosed mucin-swelling kinetics from airway cells showed that mucin diffusivity increases by ~300% with 20 mM extracellular HC[O.sub.3.sup.-] concentration. Supporting data indicate that HC[O.sub.3.sup.-] reduces free [Ca.sup.2+] concentration and decreases the amount of [Ca.sup.2+] that remains associated with mucins. The results demonstrate that HC[O.sub.3.sup.-] enhances mucin swelling and hydration by reducing [Ca.sup.2+] cross-linking in mucins, thereby decreasing its viscosity and likely increasing its transportability. In addition, HC[O.sub.3.sup.-] can function as a [Ca.sup.2+] chelator like EGTA to disperse mucin aggregates. This study indicates that poor HC[O.sub.3.sup.-] availability in CF may explain why secreted mucus remains aggregated and more viscous in affected organs. These insights bear on not only the fundamental pathogenesis in CF, but also on the process of gel mucus formation and release in general. mucus dispersion; calcium chelation; cystic fibrosis and swelling kinetics; mucin viscosity; thickness doi: 10.1152/ajplung.00180.2010.

CFTR is a highly regulated apical chloride channel of epithelial cells that is mutated in cystic fibrosis (CF). In this study, we characterized the apical stability and intracellular trafficking of wild-type and mutant CFTR in its native environment, i.e., highly differentiated primary human airway epithelial (HAE) cultures. We labeled the apical pool of CFTR and subsequently visualized the protein in intracellular compartments. CFTR moved from the apical surface to endosomes and then efficiently recycled back to the surface. CFTR endocytosis occurred more slowly in polarized than in nonpolarized HAE cells or in a polarized epithelial cell line. The most common mutation in CF, [DELTA]F508 CFTR, was rescued from endoplasmic reticulum retention by low-temperature incubation but transited from the apical membrane to endocytic compartments more rapidly and recycled less efficiently than wild-type CFTR. Incubation with small-molecule correctors resulted in [DELTA]F508 CFTR at the apical membrane but did not restore apical stability. To stabilize the mutant protein at the apical membrane, we found that the dynamin inhibitor Dynasore and the cholesterol-extracting agent cyclodextrin dramatically reduced internalization of [DELTA]F508, whereas the proteasomal inhibitor MG-132 completely blocked endocytosis of [DELTA]F508. On examination of intrinsic properties of CFTR that may affect its apical stability, we found that N-linked oligosaccharides were not necessary for transport to the apical membrane but were required for efficient apical recycling and, therefore, influenced the turnover of surface CFTR. Thus apical stability of CFTR in its native environment is affected by properties of the protein and modulation of endocytic traff~cking. cystic fibrosis; [DELTA]F508; protein trafficking; turnover; polarized cells doi:10.1152/ajplung.00016.2009

A study was conducted to evaluate whether certain gene modifiers were associated with severe liver disease in patients with cystic fibrosis (CF). Results indicated that the SERPINA1 Z allele was associated with risk of developing the disease.

Cystic fibrosis (CF) is due to mutations in the CFTR gene and is characterized by hypersecretion of the proinflammatory chemokine IL-8 into the airway lumen. Consequently, this induces the highly inflammatory cellular phenotype typical of CF. Our initial studies revealed that IL-8 mRNA is relatively stable in CF cells compared with those that had been repaired with [WT]CFTR (wild-type CFTR). Relevantly, the 3'-UTR of IL-8 mRNA contains AU-rich sequences (AREs) that have been shown to mediate posttranscriptional regulation of proinflammatory genes upon binding to ARE-binding proteins including Tristetraprolin (TTP). We therefore hypothesized that very low endogenous levels of TTP in CF cells might be responsible for the relative stability of IL-8 mRNA. As predicted, increased expression of TTP in CF cells resulted in reduced stability of IL-8 mRNA. An in vitro analysis of IL-8 mRNA stability in CF cells also revealed a TTP-induced enhancement of deadenylation causing reduction of IL-8 mRNA stability. We conclude that enhanced stability of IL-8 mRNA in TTP-deficient CF lung epithelial cells serve to drive the proinflammatory cellular phenotype in the CF lung. cytokines; chemokines; inflammation; gene regulation

The cellular mechanisms by which loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel produce cystic fibrosis (CF) lung disease remain uncertain. Defective organellar function has been proposed as an important determinant in the pathogenesis of CF lung disease. According to one hypothesis, reduced CFTR chloride conductance in organelles in CF impairs their acidification by preventing chloride entry into the organelle lumen, which is needed to balance the positive charge produced by proton entry. According to a different hypothesis, CFTR mutation hyperacidifies organelles by an indirect mechanism involving unregulated sodium efflux through epithelial sodium channels. There are reports of defective Golgi, endosomal and lysosomal acidification in CF epithelial cells, defective phagolysosomal acidification in CF alveolar macrophages, and organellar hyperacidification in CF respiratory epithelial cells. The common theme relating too high or low organellar pH to cellular dysfunction and CF pathogenesis is impaired functioning of organellar enzymes, such as those involved in ceramide metabolism and protein processing in epithelial cells and antimicrobial activity in alveolar macrophages. We review here the evidence for defective organellar acidification in CF. Significant technical and conceptual concerns are discussed regarding the validity of data showing too high/low organellar pH in CF cells, and rigorous measurements of organellar pH in CF cells are reviewed that fail to support defective organellar acidification in CF. Indeed, there is an expanding body of evidence supporting the involvement of non-CFTR chloride channels in organellar acidification. We conclude that biologically significant involvement of CFTR in organellar acidification is unlikely. cystic fibrosis transmembrane conductance regulator; lysosome; endosome; Golgi; chloride channel

Pancreatic ductal epithelium produces a HC[O.sup.-.sub.3]-rich fluid. HC[O.sup.-.sub.3] transport across ductal apical membranes has been proposed to be mediated by both SLC26-mediated [Cl.sup.-]/HC[O.sup.-.sub.3] exchange and CFTR-mediated HC[O.sup.-.sub.3] conductance, with proportional contributions determined in part by axial changes in gene expression and luminal anion composition. In this study we investigated the characteristics of apical [Cl.sup.-]/ HCO3 exchange and its functional interaction with Cftr activity in isolated interlobular ducts of guinea pig pancreas. BCECF-loaded epithelial cells of luminally microperfused ducts were alkalinized by acetate prepulse or by luminal [C1.sup.-] removal in the presence of HC[O.sup.-.sub.3]-C[O.sub.2]. Intracellular pH recovery upon luminal [Cl.sup.-] restoration (nominal [Cl.sup.-]/HC[O.sup.-.sub.3] exchange) in cAMP-stimulated ducts was largely inhibited by luminal dihydro-DIDS ([H.sub.2]DIDS), accelerated by luminal CFTR inhibitor inh-172 (CFTRinh-172), and was insensitive to elevated bath [K.sup.+] concentration. Luminal introduction of CP'TRinh-172 into sealed duct lumens containing BCECF-dextran in HC[O.sup.-.sub.3]-free, [Cl.sup.-]-rich solution enhanced cAMP-stimulated HC[O.sup.-.sub.3] secretion, as calculated from changes in luminal pH and volume. Luminal [Cl.sup.-] removal produced, after a transient small depolarization, sustained cell hyperpolarization of ~15 mV consistent with electrogenic [Cl.sup.-]/HC[O.sup.-.sub.3] exchange. The hyperpolarization was inhibited by [H.sub.2]DIDS and potentiated by CPTRinh-172. Inteflobular ducts expressed mRNAs encoding CPTR, Slc26a6, and Slc26a3, as detected by RT-PCR. Thus [Cl.sup.-]-dependent apical HC[O.sup.-sub.3] secretion in pancreatic duct is mediated predominantly by an Slc26a6-1ike [Cl.sup.-]/HC[O.sup.-.sub.3] exchanger and is accelerated by inhibition of CFTR. This study demonstrates functional coupling between Cftr and Slc26a6-1ike [Cl.sup.-]/HC[O.sup.-.sub.3] exchange activity in apical membrane of guinea pig pancreatic interlobular duct. bicarbonate; Slc26; cystic fibrosis transmembrane conductance regulator; forskolin; [H.sub.2]DIDS

Lubiprostone, a putative ClC-2 chloride channel opener, has been investigated for its effects on airway epithelia (tracheas). Lubiprostone is shown to increase submucosal gland secretion in pigs, sheep, and humans and to increase short-circuit current (SCC) in the surface epithelium of pigs and sheep. Use of appropriate blocking agents and ion-substitution experiments shows anion secretion is the driving force for fluid formation in both glands and surface epithelium. From SCC concentration-response relations, it is shown that for apical lubiprostone [K.sub.d] = 10.5 nM with a Hill slope of 1.08, suggesting a single type of binding site and, from the speed of the response, close to the apical surface, confirmed the rapid blockade by Cd ions. Responses to lubiprostone were reversible and repeatable, responses being significantly larger with ventral compared with dorsal epithelium. Submucosal gland secretion rates following basolateral lubiprostone were, respectively, 0.2, 0.5, and 0.8 nl [gl.sup.-1] [min.sup.-1] in humans, sheep, and pigs. These rates dwarf any contribution surface secretion adds to the accumulation of surface liquid under the influence of lubiprostone. Lubiprostone stimulated gland secretion in two out of four human cystic fibrosis (CF) tissues and in two of three disease controls, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis (COPD/IPF), but in neither type of tissue was the increase significant. Lubiprostone was able to increase gland secretion rates in normal human tissue in the continuing presence of a high forskolin concentration. Lubiprostone had no spasmogenic activity on trachealis muscle, making it a potential agent for increasing airway secretion that may have therapeutic utility. airway surface epithelium; airway submucosal glands; sheep, pig, and human tracheas; cystic fibrosis

Chronic bacterial airway infections are the major cause of mortality in cystic fibrosis (CF). Normal airway defenses include reflex stimulation of submucosal gland mucus secretion by sensory neurons that release substance P (SubP). CFTR is an anion channel involved in fluid secretion and mutated in CF; the role of CFTR in secretions stimulated by SubP is unknown. We used optical methods to measure SubP-mediated secretion from human submucosal glands in lung transplant tissue. Glands from control but not CF subjects responded to mucosal chili oil. Similarly, serosal SubP stimulated secretion in more than 60% of control glands but only 4% of CF glands. Secretion triggered by SubP was synergistic with vasoactive intestinal peptide and/or forskolin but not with carbachol; synergy was absent in CF glands. Pig glands demonstrated a nearly 10-fold greater response to SubP. In 10 of 11 control glands isolated by fine dissection, SubP caused cell volume loss, lumen expansion, and mucus flow, but in 3 of 4 CF glands, it induced lumen narrowing. Thus, in CF, the reduced ability of mucosal irritants to stimulate airway gland secretion via SubP may be another factor that predisposes the airways to infections., Introduction Cystic fibrosis (CF) is caused by mutations that disrupt CFTR, an anion channel that mediates fluid secretion in many epithelia. The most serious consequence of CF is respiratory failure [...]

Immortalization of human bronchial epithelial (hBE) cells often entails loss of differentiation. Bmi-1 is a protooncogene that maintains stem cells, and its expression creates cell lines that recapitulate normal cell structure and function. We introduced Bmi-1 and the catalytic subunit of telomerase (hTERT) into three non-cystic fibrosis (CF) and three [DELTA]F508 homozygous CF primary bronchial cell preparations. This treatment extended cell life span, although not as profoundly as viral oncogenes, and at passages 14 and 15, the new cell lines had a diploid karyotype. Ussing chamber analysis revealed variable transepithelial resistances, ranging from 200 to 1,200 [OMEGA] x [cm.sup.2]. In the non-CF cell lines, short-circuit currents were stimulated by forskolin and inhibited by CFTR(inh)-172 at levels mostly comparable to early passage primary cells. CF cell lines exhibited no forskolin-stimulated current and minimal CFrR(inh)-172 response. Amiloride-inhibitable and UTP-stimulated currents were present, but at lower and higher amplitudes than in primary cells, respectively. The cells exhibited a pseudostratified morphology, with prominent apical membrane polarization, few apoptotic bodies, numerous mucous secretory cells, and occasional ciliated cells. CF and non-CF cell lines produced similar levels of IL-8 at baseline and equally increased IL-8 secretion in response to IL-1[beta], TNF-[alpha], and the Toll-like receptor 2 agonist Pam3Cys. Although they have lower growth potential and more fastidious growth requirements than viral oncogene transformed cells, Bmi-1/hTERT airway epithelial cell lines will be useful for several avenues of investigation and will help fill gaps currently hindering CF research and therapeutic development. Bmi-1; cystic fibrosis transmembrane conductance regulator; inflammation; karyotype; Using chamber

Cystic fibrosis (CF) is caused by mutations in the gene producing the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR functions as a [Cl.sup.-] channel. Its dysfunction limits [Cl.sup.-] secretion and enhances [Na.sup.+] absorption, leading to viscous mucus in the airway. [Ca.sup.2+]-activated [Cl.sup.-] channels (CaCCs) are coexpressed with CFTR in the airway surface epithelia. Increases in cytosolic [Ca.sup.2+] activate the epithelial CaCCs, which provides an alternative [Cl.sup.-] secretory pathway in CF. We developed a screening assay and screened a library for compounds that could enhance cytoplasmic [Ca.sup.2+], activate the CaCC, and increase [Cl.sup.-] secretion. We found that spiperone, a known antipsychotic drug, is a potent intracellular [Ca.sup.2+] enhancer and demonstrated that it stimulates intracellular [Ca.sup.2+], not by acting in its well-known role as an antagonist of serotonin [5-HT.sub.2] or dopamine [D.sub.2] receptors, but through a protein tyrosine kinase-coupled phospholipase C-dependent pathway. Spiperone activates CaCCs, which stimulates [Cl.sup.-] secretion in polarized human non-CF and CF airway epithelial cell monolayers in vitro and in CFTR-knockout mice in vivo. In conclusion, we have identified spiperone as a new therapeutic platform for correction of defective [Cl.sup.-] secretion in CF via a pathway independent of CFTR. cystic fibrosis therapy; calcium-activated chloride channel

Irreversible destruction and widening of the airways due to acquired infections or genetic mutations as well as those of unknown cause are more severe in females. Differences between male and female anatomy, behavior, and hormonal state have been proposed to explain the increased incidence and severity in females with airway disease such as cystic fibrosis (CF); however, a mechanism to explain a sex-related difference has remained elusive. In this issue of the JCI, Coakley et al. report that elevations in the major estrogen hormone in humans-17[beta]-estradiol--reduce [Ca.sup.2+]-activated [Cl.sup.-] secretion by airway epithelial cells in culture, thereby disrupting ion and water balance (see the related article beginning on page 4025). They measure a similar diminution of nasal epithelial [Ca.sup.2+]-activated [Cl.sup.-] secretion in women with CF during the menstrual cycle phase at which 17[beta]-estradiol level is at its highest. These data suggest that for about one week of a four-week menstrual cycle, women with CF will have a reduced ability to efficiently clear airway secretions, the buildup of which is a hallmark of CF. The authors suggest that these data warrant the testing of antiestrogen therapy in females with CF and propose an alternative avenue for CF therapeutic development., Does female sex impose genetic, hormonal, and/or behavioral constraints on lung function, including a predilection to the airway destruction and widening known as bronchiectasis? In patients with cystic fibrosis (CF), [...]

The human opportunistic pathogen Pseudomonas aeruginosa is the major cause of morbidity and mortality of cystic fibrosis patients and is responsible for a variety of infections in compromised hosts. Using PCR-based signature-tagged mutagenesis, we identified a P. aeruginosa STM5437 mutant with an insertion into the PA5437 gene (called pycR for putative pyruvate carboxylase regulator). PycR inactivation results in 100 000-fold attenuation of virulence in the rat lung in vivo. PycR has the signature of a transcriptional regulator with a predicted helix-turn-helix motif binding to a typical LysR DNA binding site in the PA5436 (pycA)-PA5437 (pycR) intercistronic region. Two pyruvate carboxylase subunits (pycA and pycB) are divergently transcribed upstream of pycR. Transcriptional start sites of pycR and pycA are located at -127 and -88 bp upstream of their initiation codons with Shine--Dalgarno and putative promoter sequences containing -10 and -35 sequences. The DNA binding of PycR was confirmed by DNA mobility shift assay. Genome-wide transcriptional profiling and quantitative real-time PCR (qRT-PCR) indicated that the genes differentially regulated by PycR include two pyruvate carboxylase genes and genes necessary for lipid metabolism, lipolytic activity, anaerobic respiration and biofilm formation. PycR is a regulator with pleiotropic effects on virulence factors, such as lipase and esterase expression and biofilm formation, which are important for maintenance of P. aeruginosa in chronic lung infection.

Somatic cell gene targeting combined with nuclear transfer cloning presents tremendous potential for the creation of new, large-animal models of human diseases. Mouse disease models often fail to reproduce human phenotypes, underscoring the need for the generation and study of alternative disease models. Mice deficient for CFTR have been poor models for cystic fibrosis (CF), lacking many aspects of human CF lung disease. In this study, we describe the production of a CFTR gene--deficient model in the domestic ferret using recombinant adeno-associated virus--mediated gene targeting in fibroblasts, followed by nuclear transfer cloning. As part of this approach, we developed a somatic cell rejuvenation protocol using serial nuclear transfer to produce live CFTR-deficient clones from senescent gene-targeted fibroblasts. We transferred 472 reconstructed embryos into 11 recipient jills and obtained 8 healthy male ferret clones heterozygous for a disruption in exon 10 of the CFTR gene. To our knowledge, this study represents the first description of genetically engineered ferrets and describes an approach that may be of substantial utility in modeling not only CF, but also other genetic diseases., Introduction Cystic fibrosis (CF) is the most common autosomal recessive condition affecting white individuals. Although the CFTR gene--which encodes an epithelial chloride channel that is defective in CF--was cloned nearly [...]

Cystic fibrosis (CF) is caused by dysfunction of the CF transmembrane conductance regulator (CFTR), an anion channel whose dysfunction leads to chronic bacterial and fungal airway infections via a pathophysiological [...]

Studies have found that cystic fibrosis (CF) lung disease reflects the failure of airways defense against chronic bacterial infection. It is revealed that studies of CF cultures, transgenic mice, and CF patients indicate that the initiating event in the CF airways disease pathogenesis is reduced airway surface liquid (ASL) volume that is dehydration.

Cystic fibrosis (CF) airway disease arises from defective innate defenses, especially defective mucus clearance of microorganisms. Airway submucosal glands secrete most airway mucus, and CF airway glands do not secrete in response to VIP or forskolin. CFTR, the protein that is defective in CF, is expressed in glands, but immunocytochemistry finds the highest expression of CFTR in either the ciliated ducts or in the acini, depending on the antibodies used. CFTR is absolutely required for forskolin-mediated gland secretion; we used this finding to localize the origin of forskolin-stimulated, CFTR-dependent gland fluid secretion. We tested the hypothesis that secretion to forskolin might originate from the gland duct rather than or in addition to the acini. We ligated gland ducts at various points, stimulated the glands with forskolin, and monitored the regions of the glands that swelled. The results supported an acinar rather than ductal origin of secretion. We tracked particles in the mucus using Nomarski time-lapse imaging; particles originated in the acini and traveled toward the duct orifice. Estimated bulk flow accelerated in the acini and mucus tubules, consistent with fluid secretion in those regions, but was constant in the unbranched duct, consistent with a lack of fluid secretion or absorption by the ductal epithelium. We conclude that CFTR-dependent gland fluid secretion originates in the serous acini. The failure to observe either secretion or absorption from the CFTR and epithelial [Na.sup.+] channel (ENaC)-rich ciliated ducts is unexplained, but may indicate that this epithelium alters the composition rather than the volume of gland mucus. innate defense; mucus

The results of a three-year ethnographic study of persons with cystic fibrosis (CF) who have undergone double-lung transplant are discussed. The constant introduction of new therapeutics intersecting with social technologies of normalization are instrumental in influencing risk interpretation and patient decisions concerning the pursuit of high-risk surgeries such as organ transplant.

OBJECTIVE. It is unclear why some patients with cystic fibrosis (CF) succeed ("responders") in recovering from malnutrition and growth faltering after treatment initiation whereas others fail to do so ("nonresponders"). We conducted a study to test the hypothesis that sustained high energy intake ([up arrow] EN) and normal plasma essential fatty acid status are critical determinants of treatment responsiveness within 2 years after diagnosis of CF. METHODS. A total of 71 CF children who had pancreatic insufficiency but not meconium ileus and were enrolled in the Wisconsin CF Neonatal Screening Project were studied. Responders were defined by having achieved adequate weight gain, as indicated by a recovery of weight z score (Wtz) comparable to Wtz at birth ([Wtz.sub.BR]) within 2 years of diagnosis. [up arrow]EN and sustained normal plasma linoleic acid level ([up arrow]pLA) were defined by achieving energy intake [greater than or equal to]120% of estimated requirement for [greater than or equal to]75% of the time and maintaining plasma LA [greater than or equal to]26% of total fatty acids for [greater than or equal to]75% of the time, respectively. RESULTS. Thirty-two (68%) screened patients and 13 (54%) patients whose CF was diagnosed conventionally recovered [Wtz.sub.BR] within 2 years of diagnosis. Screened patients responded at significantly younger ages (mean/median: 6.3/4.3 months) than patients whose CF was diagnosed conventionally (mean/median: 15.8/11.8 months). Proportionately fewer screened patients (33%) achieved [up arrow]EN compared with patients whose CF was diagnosed conventionally (73%). However, more screened patients responded to [up arrow]EN and recovered [Wtz.sub.BR] (91%) than patients whose CF was diagnosed conventionally (56%), although this difference was of borderline significance. Compared with having neither [up arrow]EN nor [up arrow]pLA, the likelihood of being a responder was greatest with combined [up arrow]EN and [up arrow]pLA, followed by [up arrow]EN only. The positive associations between [up arrow]EN and [up arrow]pLA to treatment responsiveness remained significant after adjustment for neonatal screening status, baseline height and weight status, and indices of pulmonary disease severity. CONCLUSION. [up arrow] EN and [up arrow] pLA are critical in promoting adequate weight gain in children with newly diagnosed CF. Key Words cystic fibrosis, diet, energy intake, growth, height, linoleic acid, malnutrition, neonatal screening, prospective study, weight Abbreviations CF--cystic fibrosis RDA--recommended dietary allowance LA--linoleic acid [up arrow]EN--sustained high energy intake PI--pancreatic insufficiency MI--meconium ileus [Wtz.sub.BR]--weight z score at birth Wtz--weight z score Htz--height z score EER--estimated energy requirement DRI--Dietary Reference Intakes [up arrow]pLA--sustained normal plasma linoleic acid [up arrow]pLA--sustained adequate dietary linoleic acid intake [Wtz.sub.DX]--weight Z score at diagnosis [Htz.sub.DX]--height z score at diagnosis [DELTA][Wtz.sub.DX-BR]--change in weight z score from birth to diagnosis, CYSTIC FIBROSIS (CF) is a life-threatening, genetic disorder that is characterized by intestinal malabsorption, impaired growth, and lung disease. (1,2) Malnutrition is prevalent, (3-6) as indicated by the observation that [...]

Excessive neutrophil elastase activity within airways of cystic fibrosis (CF) patients results in progressive lung damage. Disruption of disulfide bonds on elastase by reducing agents may modify its enzymatic activity. Three naturally occurring dithiol reducing systems were examined for their effects on elastase activity: 1) Escherichia coli thioredoxin (Trx) system, 2) recombinant human thioredoxin (rhTrx) system, and 3) dihydrolipoic acid (DHLA). The Trx systems consisted of Trx, Trx reductase, and NADPH. As shown by spectrophotometric assay of elastase activity, the two Trx systems and DHLA inhibited purified human neutrophil elastase as well as the elastolytic activity present in the soluble phase (sol) of CF sputum. Removal of any of the three Trx system constituents prevented inhibition. Compared with the monothiols N-acetylcysteine and reduced glutathione, the dithiols displayed greater elastase inhibition. To streamline Trx as an investigational tool, a stable reduced form of rhTrx was synthesized and used as a single component. Reduced rhTrx inhibited purified elastase and CF sputum sol elastase without NADPH or Trx reductase. Because Trx and DHLA have mucolytic effects, we investigated changes in elastase activity after mucolytic treatment. Unprocessed CF sputum was directly treated with reduced rhTrx, the Trx system, DHLA, or DNase. The Trx system and DHLA did not increase elastase activity, whereas reduced rhTrx treatment increased sol elastase activity by 60%. By contrast, the elastase activity after DNase treatment increased by 190%. The ability of Trx and DHLA to limit elastase activity combined with their mucolytic effects makes these compounds potential therapies for CF. thioctic acid; serine protease; lipoic acid; human thioredoxin; mucolytic

Two study patterns are employed and a cohort of patients are enrolled to examine genes earlier involved as modifiers in cystic fibrosis. Observations reveal that the transforming growth factor Beta 1 (TGFBeta1) variations are strongly linked to pulmonary phenotypes, and the genetic change in TGFBeta1 or a nearby upstream region is a vital genetic device that alters disease acuteness and clinical consequences in cystic fibrosis.

The opportunistic human pathogen Pseudomonas aeruginosa causes persistent airway infections in patients with cystic fibrosis (CF). To establish these chronic infections, P. aeruginosa must grow and proliferate within the highly viscous sputum in the lungs of CF patients. In this study, we used Affymetrix GeneChip microarrays to investigate the physiology of P. aeruginosa grown using CF sputum as the sole source of carbon and energy. Our results indicate that CF sputum readily supports high-density P. aeruginosa growth. Furthermore, multiple signals, which reduce swimming motility and prematurely activate the Pseudomonas quinolone signal cell-to-cell signaling cascade in P. aeruginosa, are present in CF sputum. P. aeruginosa factors critical for lysis of the common CF lung inhabitant Staphylococcus aureus were also induced in CF sputum and increased the competitiveness of P. aeruginosa during polymicrobial growth in CF sputum.

Cystic Fibrosis (CF) is the most common, fatal inherited disease found in industrialized nations. CF affects multiple body systems, but has the greatest impact on the lungs and pancreas. Although there has been an increase in the number of working-age individuals with CF in the past 20 years, research on career choice, work status and work disability of individuals with CF has received very little attention. Information about the vocational potential for individuals with CF indicates limited expectation for vocational success. This paper describes the vocational status of 183 adults with CF and provides information about this group's vocational potential. Important findings of this study were: (1) the majority of participants were either working or in school; (2) those employed were working in professional, technical, managerial, clerical and sales occupations; (3) the jobs held varied in physical demands and strength ratings, and; (4) patients with skilled jobs were more likely to have maintained their positions than those with unskilled jobs. These numbers are impressive given that the majority of these individuals were sick enough to be evaluated for their candidacy for lung transplant. These data suggest that, as with most people, vocation is an important part of life, and many individuals with CF go to school and achieve in careers and work despite their declining health. Rehabilitation counselors should consider people with CF as viable candidates for successful job placement., Cystic Fibrosis (CF), an autosomal recessive disease, affects 1 in every 3,419 live births among whites and 1 in 12,163 among non-whites (Kosorok, 1996), making CF the most commonly inherited [...]

A study is conducted to investigate the epidemiology of Pseudomonas aeruginosa infection and its impact on cystic fibrosis (CF) pulmonary morbidity. The conclusion suggests that early prevention and detection of nonmucoid and mucoid P aeruginosa are critical because of early acquisition and prevalence.

Medical sociologists have often considered lay perceptions of the risks of medical interventions, yet in many empirical studies respondents are people who are not likely to be exposed to a particular intervention. Furthermore, it has been well documented that risk perceptions may change over time and with diminishing health state. This paper explores perceptions and management of the risks of organ transplantation amongst adults with cystic fibrosis (CF), the most common autosomal recessive genetic disease in the UK. Although the focus of medical research is now on providing gene replacement therapy to this group, transplantation is currently the last treatment that an adult with CF can be offered when all other treatment has failed to maintain their health. Thirty-one respondents with varying degrees of health state from a specialist CF centre were interviewed as part of a larger study concerning perceptions of health and risks of treatment. Interviews were audiotaped, transcribed and analysed using ATLAS-ti. During analysis respondents' transcripts were divided into two groups: firstly those who did not anticipate needing a transplant in the near future (if at all) and secondly those who were currently being considered for transplantation, on the transplant list, or who had already received donor organs. The paper focuses on themes arising from interview transcripts and finds that although the focus of risk differs between the two groups, the influence of luck is perceived as strong for both groups and emotion work features heavily in those undergoing the transplant process. Contrary to previous research, fears of inheriting donor characteristics are not found amongst adults with CF, but rather body components are commodified when talking of both giving and receiving organs. Keywords: Organ transplantation; Organ donation; Cystic fibrosis; Lay beliefs; UK

Byline: U. Baumann (1), J.J. Fischer (1), P. Gudowius (1), M. Lingner (1), S. Herrmann (1), B. Tummler (1), H. von der Hardt (1) Keywords: Key Words Cystic fibrosis; Azithromycin; Buccal adherence; Oropharyngeal barrier; Pseudomonas aeruginosa Abstract: Background: The oropharyngeal barrier is an innate host defence mechanism to prevent bacterial lung infection. A compromised barrier function is observed in patients with cystic fibrosis (CF) who are chronically infected with Pseudomonas aeruginosa. Macrolides are assumed to modify host defence. We investigated the oropharyngeal barrier function in CF patients treated with azithromycin (AZM). Patients and Methods: In a prospective study, eleven chronically infected children with CF were treated with long-term low-dose AZM. The oropharyngeal barrier function was assessed by adherence of P. aeruginosa (strain PACF 12-1) to buccal epithelial cells of the patients before and after therapy. Results: The mean (standard deviation, SD) buccal adherence before therapy was markedly high with 8.0 (4.8) bacteria/cell. Following therapy with AZM adherence decreased in all patients by 70% or 5.6 to 2.4 (1.1) bacteria/cell (p = 0.007), representing close to normal levels (1.2 +- 0.6). Conclusion: Long-term low-dose AZM therapy may improve the compromised oropharyngeal barrier function in patients with CF, opening new perspectives for early treatment of P. aeruginosa infection in CF. Author Affiliation: (1) Dept. of Pediatric Pneumology and Neonatology, Hannover Medical School, D-30623 Hannover, Germany Phone: (+49/511) 532-3251, Fax: -9125, e-mail: baumann.ulrich@mh-hannover.de, DE Article note: Received: February 28, 2000 * Revision accepted: August 16, 2000