Hector H. Gutierrez

Nitric oxide regulation of superoxide-dependent lung injury: Oxidant-protective actions of endogenously produced and exogenously administered nitric oxide

The influence of endogenous cell .NO production and .NO derived from exogenous sources on oxidant injury to cultured fetal rat lung alveolar epithelium and an animal model of pulmonary oxidant injury was examined. Confluent fetal rat alveolar epithelial cell monolayers were stimulated to produce .NO after treatment with a combination of cytokines (IL-1 beta, TNF-alpha, IFN-gamma), LPS and zymosan-activated serum (CZ). Cell injury, assessed by 14C-adenine release, was significantly increased compared to basal and CZ-induced cells after inhibition of .NO synthesis by L-NMMA. Cell monolayer macromolecule barrier function was determined by the rate of diffusion of 125I-albumin from the apical to basolateral side of monolayers. Following exposure to CZ and/or O2.- generated by xanthine oxidase + lumazine (XO), endogenous cell .NO production and exogenously administered .NO (from .NO donors S-nitrosyl-glutathione and S-nitroso-N-acetylpenicillamine) significantly inhibited the increased monolayer permeability induced by exposure to reactive oxygen species. Furthermore, inhalation of 5-10 ppm of .NO significantly reduced the toxicity of > 95% oxygen to adult rats. We conclude that when cultured pulmonary epithelial cells and lung tissue in vivo are subjected to inflammatory mediators or acute oxidative stress, .NO can play a protective role by inhibiting O2.(-)-dependent toxicity.

Oxygen Radical-Nitric Oxide Reactions in Vascular Diseases

Publisher Summary The principal challenge in the research of radical biology lies in developing a solid causal relationship between the tissue productions of various reactive species, long recognized to have potent and toxic target molecule reactions, and their contribution to cell or tissue dysfunction. Not until this is accomplished can a rational therapeutic strategy for oxidant tissue injury be devised. These dilemmas amplify the immense challenge that is faced upon in development of a clear understanding of the multifaceted role that nitric oxide (NO) plays in vascular disease. The high rate of production and broad distribution of sites of production of NO, combined with its facile direct and indirect reactions with metalloproteins, thiols, and various oxygen radical species ensure that NO plays a central role in regulating vascular physiological and cellular homeostasis as well as critical intravascular free radical and oxidant reactions. This concept is emphasized in this chapter, using atherosclerosis as a prime example of the central role that reactive species play in vascular diseases. The chapter describes how superoxide anion (O 2− ) “inactivates” the vasorelaxant actions of NO in atherosclerotic vessels, leading to impaired endothelial cell (EC)-dependent relaxation and a propensity for vasospasm. The alterations in vascular reactivity associated with atherosclerosis are related to changes in EC-dependent mechanisms of relaxation. Acetylcholine and other EC agonists normally promote the relaxation of isolated vascular ring segments by stimulating the production of NO. Nitric oxide diffuses to underlying vascular smooth muscle cells, where it activates soluble guanylate cyclase and induces vessel relaxation via cGMP-dependent mechanisms.

Baseline Characteristics and Factors Associated With Nutritional and Pulmonary Status at Enrollment in the Cystic Fibrosis EPIC Observational Cohort

The EPIC Observational Study is an ongoing prospective cohort study investigating risk factors for and clinical outcomes associated with early Pseudomonas aeruginosa (Pa) acquisition in young children with cystic fibrosis (CF).

Improving the quality of care for patients with cystic fibrosis.

Purpose of review Improvement in cystic fibrosis (CF) outcomes over the past 50 years has been dramatic. This article describes the factors that have contributed to the recent acceleration in this improvement and the important role of the Cystic Fibrosis Foundation. Recent findings Initiatives to improve CF care over the past decade include the refinement of a sophisticated patient registry that allows a comparison of center processes and outcomes; development of evidence-based and consensus-based guidelines regarding standards of care; cultural transformation, including the training of care center teams in a systems-oriented approach to quality improvement; data transparency; and encouragement of a patient-centered and family-centered orientation. Cystic Fibrosis Foundation initiatives have promoted an increase in the consistent provision of evidence-based care and the promulgation of innovative, proactive therapeutic approaches. Unfortunately, so far most of these accomplishments have not been documented in peer-reviewed research articles, but rather in platform presentations at national meetings, meeting abstracts, data reports to center directors, and published reports from individual centers. Summary While several new medications for CF lung disease have been introduced in the last decade, improvements in outcomes have been largely due to refinements in the delivery of care. At this point, the most efficient and reliably effective technique for promoting further improvement still needs to be identified. Recent discussions have centered on attempts at new innovative approaches that utilize more selective teaching of relevant systems-based quality improvement methods in the specific CF environment.

Rapid Onset of Iatrogenic Adrenal Insufficiency in a Patient with Cystic Fibrosis-Related Liver Disease Treated with Inhaled Corticosteroids and a Moderate CYP3A4 Inhibitor

Objective: To report the rapid onset of adrenal insufficiency and subsequent development of Cushing syndrome precipitated by a CYP3A4-mediated drug-drug interaction that may have been enhanced by the presence of cystic fibrosis (CF)-related liver disease. Case Summary: A 9-year-old girl with CF and cirrhosis experienced a decline in lung function that led to a diagnosis of asthma. After initiation of asthma therapy with inhaled fluticasone 110 μg/actuation, the patient experienced improvement in lung function to baseline. Seven weeks after the initiation of inhaled fluticasone, she developed vaginal candidiasis and was prescribed fluconazole 100 mg/day, a CYP3A4 inhibitor. Three days after starting fluconazole, she developed polyuria and polydipsia and was found to have severe hyperglycemia, which led to the diagnosis of Cushing syndrome. Fluticasone was discontinued, and the patients adrenal function normalized. Discussion: Patients with CF are commonly prescribed complex medication regimens that may affect drug metabolism. CYP3A4 inhibitors may significantly decrease metabolic clearance in patients using chronic inhaled corticosteroids. Iatrogenic Cushing syndrome has been reported in patients with CF treated concomitantly, and for extended duration, with inhaled corticosteroids and CYP3A4 inhibitors. This case highlights rapid onset of adrenal insufficiency in a patient with CF-related liver disease treated briefly with a moderate CYP3A4 inhibitor. Use of the Horn drug interaction probability scale indicates that the interaction between fluticasone and fluconazole was probable. Conclusions: CYP3A4-mediated drug interactions represent a significant risk in patients treated with long-term inhaled corticosteroids. The presence of clinically significant CF-related liver disease may enhance this risk.

Spiritual coping predicts 5-year health outcomes in adolescents with cystic fibrosis.

BACKGROUND Positive spiritual coping in adolescent patients with cystic fibrosis (CF) is associated with better emotional functioning, but its role in health outcomes is unknown. METHODS Adolescents diagnosed with CF (n = 46; M = 14.7 years) reported on their use of positive and negative spiritual coping. Measures of nutrition status (BMIp), pulmonary function (%FEV1), and hospitalizations were obtained for a five-year follow up period. Changes in BMIp and %FEV1 scores were estimated with hierarchical linear models; days hospitalized were modeled with negative binomial regression. RESULTS Positive spiritual coping was associated with slower decline in pulmonary function, stable vs. declining nutritional status, and fewer days hospitalized over the five-year period. Negative spiritual coping was associated with higher BMI percentile at baseline, but not with health outcomes over time. CONCLUSIONS These results suggest that positive spiritual coping plays a key role in maintaining long-term health of adolescent patients with CF.

Adherence to Airway Clearance Therapy in Pediatric Cystic Fibrosis: Socioeconomic Factors and Respiratory Outcomes

The evidence linking socioeconomic status (SES) and adherence in cystic fibrosis (CF) is inconclusive and focused on medication uptake. We examined associations between SES, adherence to airway clearance therapy (ACT), and CF respiratory outcomes.

Sustained improvement in nutritional outcomes at two paediatric cystic fibrosis centres after quality improvement collaboratives

Objective To describe the characteristics of sustained improved nutritional outcomes through the use of quality improvement (QI) methodology. Design Retrospective analysis of a QI intervention in two institutions, implemented as part of larger national collaboratives. Setting Paediatric cystic fibrosis (CF) programmes in academic centres in Alabama and Illinois. Participants All paediatric patients enrolled in the CF Foundation (CFF) Patient Data Registry were included. Interventions Improved and sustained nutrition outcomes occurred through implementation of the CFF practice guidelines for CF nutrition management via care delivery processes, nutritional interventions, team engagement and data display. Measurement Mean body mass index (BMI) percentile, percentage of patients less than 50th percentile and percentage less than 10th percentile for all patients aged 2–20 years were tracked through run charts and statistical process control charts. Mann–Whitney U and χ2 tests were used to determine significance between each centre and national outcomes. Results Each centre achieved rapid improvement in mean BMI percentile in patients, one centre rising from the 40th percentile in 2001 to the 49th percentile in 2003, the other rising from the 37th percentile in 2003 to the 45th percentile in 2004. These centres have also maintained improved nutritional outcomes, so that they were at the 60th and 55th percentiles, respectively, in 2011. Sustained improvement was accomplished through QI methodology, use of data as a driver for improvement and a change in culture. Conclusions Participation in collaboratives led to improved nutrition outcomes while a strong culture of QI facilitated sustained improvement.

Genetic and Reproductive Knowledge Among Adolescents and Adults With Cystic Fibrosis

Studies1,2 have shown that cystic fibrosis (CF) patients have limited knowledge of the genetics of CF. Previously, there was limited need to communicate this information: few CF patients lived to adulthood, and most who did could not reproduce.1,2 Genetic counseling focused on the patient’s parents, who were counseled about the recurrence risk at the time of the diagnosis. Today, CF is a disease of adulthood.3 In 2002, 40% of CF patients in the United States were 18 years old; by 2010, it will be 50%. Together with advances in assisted reproductive technology, reproduction and recurrence risk are now important issues for adolescent and young adult CF patients.3–6 A 19-item questionnaire was developed from the results of prior semistructured interviews with 18 CF patients aged 16 to 25 years. Knowledge-based questions (medical issues, inheritance, and reproductive options/risks) as well as communication patterns (preferred resources for learning about CF and preferred people with whom to talk about reproductive issues) were addressed. Recruited from the University of Alabama CF clinic population, 51 patients aged 15 to 29 years (mean, 21 years), 24 male (47%) and 27 female (53%), completed the questionnaire. The study was approved by the University of Alabama Institutional Review Board. Regarding autosomal recessive inheritance, only 33% knew that two carriers have a 25% chance of having a child with CF, and 25% knew that two carriers have a 50% chance of having a child who is a carrier. However, 82% knew that two carriers could have a child who did not have CF, and 52% knew that two carriers could have a child who did not carry CF. On their own reproductive risks, 59% knew that a CF patient had a 0% chance of having a child with CF if their partner was not a carrier, but only 26% knew that all their children would be carriers even if their partner was not a carrier. In the scenario of a CF patient with a CF carrier partner, 44% knew that a child had a 50% chance of having CF, and 24% knew that a child had a 50% chance of being a CF carrier. Most patients knew about their reproductive potential, as 96% responded that CF patients are able to have children. However, when asked about whether the chance for having children was different for male and female patients with CF, 65% answered that it was more difficult for men, 8% that it was more difficult for women, and 27% answered “not sure.” While 62% reported that they knew that there were options for male CF patients who wanted to have children, only 26% knew of assisted reproductive technology. Despite widespread availability, the lack of knowledge of adolescents and young adults with CF about the genetics of their disease continues. Furthermore, these patients are unaware of both modern technologies that could enable them to have biological children and the risk of those children having CF. This study illustrates the changing needs of patient education as medical knowledge progresses. CF patients would benefit from further genetic knowledge and counseling to enable them to make informed decisions about reproduction as they mature into adulthood.

Risk stratification model to detect early pulmonary disease in infants with cystic fibrosis diagnosed by newborn screening.

The clinical benefit of newborn screening (NBS) for cystic fibrosis (CF) has been primarily nutritional, with less overt respiratory impact. Identification of risk factors for infant CF lung disease could facilitate targeted interventions to improve pulmonary outcomes.