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Seasonal Antimicrobial Activity of the Airway: Post-Hoc Analysis of a Randomized Placebo-Controlled Double-Blind Trial.
Vargas Buonfiglio, LG, Vanegas Calderon, OG, Cano, M, Simmering, JE, Polgreen, PM, Zabner, J, Gerke, AK, Comellas, AP
Nutrients. 2020;(9)
Abstract
BACKGROUND It is widely unknown why respiratory infections follow a seasonal pattern. Variations in ultraviolet B (UVB) light during seasons affects cutaneous synthesis of vitamin D3. Serum vitamin D concentration influences the expression of airway surface liquid (ASL) antimicrobial peptides such as LL-37. OBJECTIVE We sought to determine the effect of seasons on serum vitamin D levels and ASL antimicrobial activity. METHODS Forty participants, 18-60 years old, were randomized 1:1 to receive 90 days of 1000 IU vitamin D3 or placebo. We collected ASL via bronchoscopy and measured serum 25(OH) vitamin D from participants before and after intervention across seasons. We measured ASL antimicrobial activity by challenging samples with bioluminescent Staphylococcus aureus and measured relative light units (RLUs) after four minutes. We also investigated the role of LL-37 using a monoclonal neutralizing antibody. RESULTS We found that participants, prior to any intervention, during summer-fall (n = 20) compared to winter-spring (n = 20) had (1) decreased live bacteria after challenge (5542 ± 175.2 vs. 6585 ± 279 RLU, p = 0.003) and (2) higher serum vitamin D (88.25 ± 24.25 vs. 67.5 ± 45.25 nmol/L, p = 0.026). Supplementation with vitamin D3 increased vitamin D levels and restored ASL antimicrobial activity only during the winter-spring. The increased ASL antimicrobial activity seen during the summer-fall was abrogated by adding the LL-37 neutralizing antibody. CONCLUSION ASL kills bacteria more effectively during the summer-fall compared to the winter-spring. Supplementation of vitamin D during winter-spring restores ASL antimicrobial activity by increasing the expression of antimicrobial peptides including LL-37.
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The aetiology of diarrhoea, pneumonia and respiratory colonization of HIV-exposed infants randomized to breast- or formula-feeding.
Zash, RM, Shapiro, RL, Leidner, J, Wester, C, McAdam, AJ, Hodinka, RL, Thior, I, Moffat, C, Makhema, J, McIntosh, K, et al
Paediatrics and international child health. 2016;(3):189-97
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BACKGROUND Diarrhoea and pneumonia are common causes of childhood death in sub-Saharan Africa but there are few studies describing specific pathogens. OBJECTIVES The study aimed to describe the pathogens associated with diarrhoea, pneumonia and oropharyngeal colonization in children born to HIV-infected women (HIV-exposed infants). METHODS The Mashi Study randomized 1200 HIV-infected women and their infants to breastfeed for 6 months with ZDV prophylaxis or formula-feed with 4 weeks of ZDV. Children were tested for HIV by PCR at 1, 4, 7, 9 and 12 months and by ELISA at 18 months. Pre-defined subsets of children were sampled during episodes of diarrhoea (n = 300) and pneumonia (n = 85). Stool was tested for bacterial pathogens, rotavirus and parasites. Children with pneumonia underwent bacterial blood culture, and testing of nasopharyngeal aspirates for viral pathogens by PCR. Oropharyngeal swabs were collected from a consecutive subset of 561 infants at the routine 3-month visit for bacterial culture. RESULTS The median age (range) at sampling was 181 days for diarrhoea (0-730) and 140 days for pneumonia (2-551). Pathogens were identified in 55 (18%) children with diarrhoea and 32 (38%) with pneumonia. No differences in pathogens by child HIV status (HIV-infected vs HIV-uninfected) or feeding strategy were identified. Campylobacter was the most common diarrhoeal pathogen (7%). Adenovirus (22%) and other viruses (19%) were the primary pathogens isolated during pneumonias. More formula-fed infants had oropharyngeal colonization by pathogenic Gram-negative bacteria (16.8% vs 6.2%, P = 0.003), which was associated with a non-significant increased risk of pneumonia (OR 2.2, 95% CI 0.8-5.7). CONCLUSION A trend toward oropharyngeal bacterial colonization was observed in formula-fed infants. Although viruses were most commonly detected during pneumonia, respiratory colonization by Gram-negative bacteria may have contributed to pneumonia in formula-fed infants.
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Secondhand smoke exposure induces acutely airway acidification and oxidative stress.
Kostikas, K, Minas, M, Nikolaou, E, Papaioannou, AI, Liakos, P, Gougoura, S, Gourgoulianis, KI, Dinas, PC, Metsios, GS, Jamurtas, AZ, et al
Respiratory medicine. 2013;(2):172-9
Abstract
Previous studies have shown that secondhand smoke induces lung function impairment and increases proinflammatory cytokines. The aim of the present study was to evaluate the acute effects of secondhand smoke on airway acidification and airway oxidative stress in never-smokers. In a randomized controlled cross-over trial, 18 young healthy never-smokers were assessed at baseline and 0, 30, 60, 120, 180 and 240 min after one-hour secondhand smoke exposure at bar/restaurant levels. Exhaled NO and CO measurements, exhaled breath condensate collection (for pH, H(2)O(2) and NO(2)(-)/NO(3)(-) measurements) and spirometry were performed at all time-points. Secondhand smoke exposure induced increases in serum cotinine and exhaled CO that persisted until 240 min. Exhaled breath condensate pH decreased immediately after exposure (p < 0.001) and returned to baseline by 180 min, whereas H(2)O(2) increased at 120 min and remained increased at 240 min (p = 0.001). No changes in exhaled NO and NO(2)/NO(3) were observed, while decreases in FEV(1) (p < 0.001) and FEV(1)/FVC (p < 0.001) were observed after exposure and returned to baseline by 180 min. A 1-h exposure to secondhand smoke induced airway acidification and increased airway oxidative stress, accompanied by significant impairment of lung function. Despite the reversal in EBC pH and lung function, airway oxidative stress remained increased 4 h after the exposure. Clinical trial registration number (EudraCT): 2009-013545-28.
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Reduced sodium transport with nasal administration of the prostasin inhibitor camostat in subjects with cystic fibrosis.
Rowe, SM, Reeves, G, Hathorne, H, Solomon, GM, Abbi, S, Renard, D, Lock, R, Zhou, P, Danahay, H, Clancy, JP, et al
Chest. 2013;(1):200-207
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BACKGROUND Prostasin, a trypsin-like serine protease, is a channel-activating protease and major regulator of epithelial sodium channel-mediated sodium absorption. Its direct inhibition by camostat represents a potential approach to inhibiting sodium transport in cystic fibrosis (CF). METHODS To determine whether a topical formulation of camostat represents an efficacious and tolerable approach to reducing Na+ transport in the CF airway, we conducted a two-part randomized, double-blind, placebo-controlled, crossover, ascending single-dose study to evaluate the pharmacodynamics, safety, and pharmacokinetics of camostat administered through a nasal spray pump in subjects with CF. Nasal potential difference (PD) was measured before and after treatment, and safety and pharmacokinetics were assessed by a standardized approach. RESULTS In part 1, nine subjects were enrolled, and six completed crossover dosing at the maximally tolerated dose. The change in maximal (most polarizing) basal PD 2 h following administration of camostat was +13.1 mV (1.6-mg dose group) compared with -8.6 mV following placebo (P<.005). Intrasubject change in Ringer and amiloride-sensitive PDs exhibited similar and consistent responses. Bayesian analysis in an additional six subjects in part 2 estimated a dose of 18 μg/mL to provide 50% of the maximum effect. There was no significant change in chloride transport or total nasal symptom score, nasal examination rating, and laboratory parameters. CONCLUSIONS This study establishes the proof of concept that a reduction in sodium transport in the human CF airway can be achieved through inhibition of prostasin activity, identifying a potential therapeutic target in the disease. TRIAL REGISTRATION ClinicalTrials.gov; No.: NCT00506792; URL: www.clinicaltrials.gov.
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[Effect of probiotics on respiratory tract pathogen colonization in neonates undergoing mechanical ventilation].
Li, XC, Wang, JZ, Liu, YH
Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics. 2012;(6):406-8
Abstract
OBJECTIVE To study the effect of mouth-fed probiotics on pathogenic bacteria colonization of the oropharynx and lower respiratory tract in neonates undergoing mechanical ventilation. METHODS Randomized control method was employed to divide the neonates undergoing mechanical ventilation into probiotics (n=82) and control groups (n=83). The control group received routine treatment. The probiotics group was administered with oral probiotics in addition to routine treatment. The number of pathogenic bacteria colonized on the oropharynx and lower respiratory tract, and the number of the bacterial strain of ventilator-associated pneumonia (VAP) in the two groups were examined. The timing of the bacteria colonization and VAP occurrence were also examined. RESULTS The probiotics group presented a lower bacterial strain colonization rate of the oropharynx pathogenic bacteria than the control group (35% vs 51%; P<0.05). The colonization time of pathogenic bacteria of the oropharynx and lower respiratory tract, and the time of VAP occurrence lagged behind in the probiotics group compared with that the control group (P<0.05). No adverse reaction caused by probiotics was found. CONCLUSIONS Probiotics administration is effective in decreasing pathogenic bacteria colonization on the oropharynx, in postponing the pathogenic bacteria colonization on the oropharynx and lower respiratory tract and in delaying the occurrence of VAP in neonates undergoing mechanical ventilation.
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Impact of coenzyme Q-10 on parameters of cardiorespiratory fitness and muscle performance in older athletes taking statins.
Deichmann, RE, Lavie, CJ, Dornelles, AC
The Physician and sportsmedicine. 2012;(4):88-95
Abstract
Many older athletes take statins, which are known to have potential for muscle toxicity. The adverse effects of statins on muscles and the influence thereof on athletic performance remain uncertain. Coenzyme Q-10 (CoQ10) may improve performance and reduce muscle toxicity in older athletes taking statins. This trial was designed to evaluate the benefits of CoQ10 administration for mitochondrial function in this population. Twenty athletes aged ≥ 50 years who were taking stable doses of statins were randomized to receive either CoQ10 (200 mg daily) or placebo for 6 weeks in a double-blind, placebo-controlled, crossover study to evaluate the impact of CoQ10 on the anaerobic threshold (AT). Several secondary endpoints, including muscle function, cardiopulmonary exercise function, and subjective feelings of fitness, were also assessed. The mean (SD) change in AT from baseline was -0.59 (1.2) mL/kg/min during placebo treatment and 2.34 (0.8) mL/kg/min during CoQ10 treatment (P = 0.116). The mean change in time to AT from baseline was significantly greater during CoQ10 treatment than during placebo treatment (40.26 s vs 0.58 s, P = 0.038). Furthermore, muscle strength as measured by leg extension repetitions (reps) increased significantly during CoQ10 treatment, with a mean (SD) increase from baseline of 1.73 (2.9) reps during placebo treatment versus 3.78 (5.0) reps during CoQ10 treatment (P = 0.031). Many other parameters also tended to improve in response to CoQ10 treatment. Treatment with CoQ10 improved AT in comparison with baseline values in 11 of 19 (58%) subjects and in comparison with placebo treatment values in 10 of 19 (53%) subjects. Treatment with CoQ10 (200 mg daily) did not significantly improve AT in older athletes taking statins. However, it did improve muscle performance as measured by time to AT and leg strength (quadriceps muscle reps). Many other measures of mitochondrial function also tended to improve during CoQ10 treatment.
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Supplementation with fatty acids influences the airway nitric oxide and inflammatory markers in patients with cystic fibrosis.
Keen, C, Olin, AC, Eriksson, S, Ekman, A, Lindblad, A, Basu, S, Beermann, C, Strandvik, B
Journal of pediatric gastroenterology and nutrition. 2010;(5):537-44
Abstract
OBJECTIVES To obtain a balance in the fatty acid (FA) metabolism is important for the inflammatory response and of special importance in cystic fibrosis (CF), which is characterized by impaired FA metabolism, chronic inflammation, and infection in the airways. Nitric oxide (NO) has antimicrobial properties and low nasal (nNO) and exhaled NO (FENO), commonly reported in CF that may affect bacterial status. The present study investigates the effect of different FA blends on nNO and FENO and immunological markers in patients with CF. PATIENTS AND METHODS Forty-three patients with CF and "severe" mutations were consecutively enrolled in a randomized double-blind placebo-controlled study with 3 FA blends containing mainly n-3 or n-6 FA or saturated FA acting as placebo. FENO, nNO, serum phospholipid concentrations of FA, and biomarkers of inflammation were measured before and after 3 months of supplementation. RESULTS Thirty-five patients in clinically stable condition completed the study. The serum phospholipid FA pattern changed significantly in all 3 groups. An increase of the n-6 FA, arachidonic acid, was associated with a decrease of FENO and nNO. The inflammatory biomarkers, erythrocyte sedimentation rate, and interleukin-8 decreased after supplementation with n-3 FA and erythrocyte sedimentation rate increased after supplementation with n-6 FA. CONCLUSIONS This small pilot study indicated that the composition of dietary n-3 and n-6 FA influenced the inflammatory markers in CF. FENO and nNO were influenced by changes in the arachidonic acid concentration, supporting previous studies suggesting that both the lipid abnormality and the colonization with Pseudomonas influenced NO in the airways.
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Effect of inhaled corticosteroids on small airways in asthma: investigation using impulse oscillometry.
Yamaguchi, M, Niimi, A, Ueda, T, Takemura, M, Matsuoka, H, Jinnai, M, Otsuka, K, Oguma, T, Takeda, T, Ito, I, et al
Pulmonary pharmacology & therapeutics. 2009;(4):326-32
Abstract
BACKGROUND Small airways appear to have an important role in asthma. Hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP) has ultrafine particles and accordingly greater deposition in the small airways than chlorofluorocarbon (CFC)-BDP. Impulse oscillometry systems (IOS), a new and non-invasive measure of pulmonary function, can examine the resistance of total (R5), large (R20), and small airways (R5-R20) separately, and low-frequency reactance area (AX), also considered a measure of small airways dysfunction. METHODS Mild-to-moderate asthmatics who were inhaled corticosteroid naïve were randomized to receive 200 mcg HFA-BDP bid (n 1/4 26) or 400 mcg CFC-BDP bid (n 1/4 12) for 12 weeks in an open-label manner. Following baseline measurements, IOS and spirometry were repeated every 4 weeks, and methacholine challenge to separately assess airway sensitivity and airway reactivity and lung volumes at 12 weeks. RESULTS Moderate correlations were found between R5-R20 or AX and spirometry and lung volume indices of small airways, and between R20 and peak expiratory flow at baseline. The two groups did not significantly differ in baseline clinical or functional parameters. At 12 weeks, all IOS indices improved in the HFA-BDP group, whereas all but R5-R20 improved with CFC-BDP. R5-R20 and AX progressively improved with HFA-BDP; these changes achieved statistical significance at 12 weeks versus the CFC-BDP group. Other IOS and spirometry indices failed to show such trends. HFA-BDP significantly attenuated methacholine airway sensitivity; the degree of this attenuation strongly correlated with R5-R20 and AX baseline values, and with improvement of AX with treatment. CONCLUSION HFA-BDP is an effective treatment of small airways in asthma. Prolonged treatment provides a progressive effect over time, which is associated with an attenuation of airway responsiveness.
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Cardiopulmonary responses to treadmill and cycle ergometry exercise in patients with peripheral vascular disease.
Tuner, SL, Easton, C, Wilson, J, Byrne, DS, Rogers, P, Kilduff, LP, Kingsmore, DB, Pitsiladis, YP
Journal of vascular surgery. 2008;(1):123-30
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BACKGROUND Peripheral arterial disease (PAD) presenting as intermittent claudication (IC) is routinely assessed as the distance or time walked to the onset of pain, which often occurs before significant cardiopulmonary stress and is subject to confounding factors such as increased body mass and altered gait. Thus, where exercise-induced cardiovascular stress is desirable, such as in cardiac stress testing or clinical trials, an alternative modality of exercise is required. Cycling will circumvent several of the associated problems of treadmill walking and may provide an alternative preferable method of exercise, although there is limited information on the physiologic response of patients with PAD to cycling. This study compared the peak cardiorespiratory responses and the repeatability of cycling and treadmill exercise in patients with PAD. METHODS Ten men (mean age, 54 +/- 10 years) with stable IC completed two incremental exercise tests to the limit of tolerance on a treadmill and a cycle ergometer after familiarization with the outcome measures of exercise duration, work performed, respiratory gas exchange variables using continuous breath-by-breath measurement, heart rate, and ratings of perceived pain. RESULTS Both methods of exercise assessment revealed high reproducibility in terms of absolute claudication time (treadmill, r = 0.95; cycle, r = 0.91), time to volitional fatigue (treadmill, r = 0.96; cycle, r = 0.91), and cardiopulmonary exercise responses such as the lactate threshold (treadmill, r = 0.95; cycle, r = 0.94), peak heart rate (treadmill, r = 0.94; cycle, r = 0.96), and peak oxygen uptake (treadmill, r = 0.98; cycle, r = 0.87). Cycling induced significantly higher cardiopulmonary responses (peak heart rate, peak carbon dioxide output, peak minute ventilation, and respiratory exchange ratio) than treadmill exercise. There was no difference in time to volitional fatigue or in absolute claudication time between exercise modalities. CONCLUSION These results demonstrate that exercise testing using cycling offers an alternative method of cardiopulmonary testing for patients with IC that is equally reliable and reproducible to treadmill walking. Cycling may be preferable to treadmill exercise because it induces greater cardiopulmonary and metabolic responses and is better tolerated by patients.
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Echinacea purpurea and mucosal immunity.
Hall, H, Fahlman, MM, Engels, HJ
International journal of sports medicine. 2007;(9):792-7
Abstract
This investigation examined the effects of Echinacea purpurea on mucosal immunity and the incidence and duration of upper respiratory tract infection (URTI). 32 subjects completed an exercise protocol known to affect mucosal immunity. Saliva was collected prior to and five minutes after completion of exercise testing. Subjects then took either a placebo (C) or Echinacea supplement (E) for 4 weeks and the testing procedure was repeated. Each time, s-IgA concentrations and saliva flow rate were measured and the secretion rate of s-IgA was calculated. In addition, standard logs indicating symptoms of URTI were completed throughout the study. Both groups demonstrated significant exercise induced reductions in s-IgA (C - 69 %; E - 43 %) and the secretion rate of s-IgA (C - 79 %; E - 53 %) at the beginning of the study (p < 0.05). Following the 4-week intervention, only the control group experienced the post intervention decrease in s-IgA (C - 45 %; E + 7 %) and the secretion rate of s-IgA (C - 45 %; E - 7 %). Further, while there was no significant difference in the number of URTI between groups, the reported duration was significantly different (C 8.6 days vs. E 3.4 days). The results suggest that Echinacea may attenuate the mucosal immune suppression known to occur with intense exercise and reduce the duration of URTI that subjects incur.