Distribution of airway narrowing during hyperpnea-induced bronchoconstriction in guinea pigs

Increasing minute ventilation of dry gas shifts the principal burden of respiratory heat and water losses from more proximal airway to airways farther into the lung. If these local thermal transfers determine the local stimulus for bronchoconstriction, then increasing minute ventilation of dry gas might also extend the zone of airway narrowing farther into the lung during hyperpnea-induced bronchoconstriction (HIB). We tested this hypothesis by comparing tantalum bronchograms in tracheostomized guinea pigs before and during bronchoconstriction induced by dry gas hyperpnea, intravenous methacholine, and intravenous capsaicin. In eight animals subjected to 5 min of dry gas isocapnic hyperpnea [tidal volume (VT) = 2-5 ml, 150 breaths/min], there was little change in the diameter of the trachea or the main stem bronchi up to 0.75 cm past the main carina (zone 1). In contrast, bronchi from 0.75 to 1.50 cm past the main carina (zone 2) narrowed progressively at all minute ventilations greater than or equal to 300 ml/min (VT = 2 ml). More distal bronchi (1.50-3.10 cm past the main carina; zone 3) did not narrow significantly until minute ventilation was raised to 450 ml/min (VT = 3 ml). The estimated VT during hyperpnea needed to elicit a 50% reduction in airway diameter was significantly higher in zone 3 bronchi [4.3 +/- 0.8 (SD) ml] than in zone 2 bronchi (3.5 +/- 1.1 ml, P less than 0.012).(ABSTRACT TRUNCATED AT 250 WORDS)     

Rapid effects of extrafine beclomethasone dipropionate/formoterol fixed combination inhaler on airway inflammation and bronchoconstriction in asthma: a randomised controlled trial

Background

Airway Bypass is a catheter-based, bronchoscopic procedure in which new passageways are created that bypass the collapsed airways, enabling trapped air to exit the lungs. The Exhale Airway Stents for Emphysema (EASE) Trial was designed to investigate whether Exhale^® Drug-Eluting Stents, placed in new passageways in the lungs, can improve pulmonary function and reduce breathlessness in severely hyperinflated, homogeneous emphysema patients (NCT00391612).

Methods/Design

The multi-center, randomized, double-blind, sham-controlled trial design was posted on http://www.clinicaltrials.gov in October 2006. Because Bayesian statistics are used for the analysis, the proposed enrollment ranged from 225 up to 450 subjects at up to 45 institutions. Inclusion criteria are: high resolution CT scan with evidence of homogeneous emphysema, post-bronchodilator pulmonary function tests showing: a ratio of FEV₁/FVC < 70%, FEV₁≤50% of predicted or FEV₁ < 1 liter, RV/TLC≥0.65 at screening, marked dyspnea score ≥2 on the modified Medical Research Council scale of 0-4, a smoking history of at least 20 pack years and stopped smoking for at least 8 weeks prior to enrollment. Following 16 to 20 supervised pulmonary rehabilitation sessions, subjects were randomized 2:1 to receive either a treatment (Exhale^® Drug-Eluting Stent) or a sham bronchoscopy. A responder analysis will evaluate the co-primary endpoints of an FVC improvement ≥12% of the patient baseline value and modified Medical Research Council dyspnea scale improvement (reduction) ≥1 point at the 6-month follow-up visit.

Discussion

If through the EASE Trial, Airway Bypass is shown to improve pulmonary function and reduce dyspnea while demonstrating an acceptable safety profile, then homogeneous patients will have a minimally invasive treatment option with meaningful clinical benefit.

Trial Registration

ClinicalTrials.gov: NCT00391612     

Nonlinearity of respiratory mechanics during bronchoconstriction in mice with airway inflammation.

Respiratory system resistance (R) and elastance (E) are commonly estimated by fitting the linear equation of motion P = EV + RV + P0 (Eq. 1) to measurements of respiratory pressure (P), lung volume (V), and flow (V). However, the respiratory system is unlikely to behave linearly under many circumstances. We determined the importance of respiratory system nonlinearities in two groups of mechanically ventilated Balb/c mice [controls and mice with allergically inflamed airways (ova/ova)], by assessing the impact of the addition of nonlinear terms (E2V2 and R2V(V)) on the goodness of model fit seen with Eq. 1. Significant improvement in fit (51.85 +/- 4.19%) was only seen in the ova/ova mice during bronchoconstriction when the E2V2 alone was added. An improvement was also observed with addition of the E2V2 term in mice with both low and high lung volumes ventilated at baseline, suggesting a volume-dependent nonlinearity of E. We speculate that airway closure in the constricted ova/ova mice accentuated the volume-dependent nonlinearity by decreasing lung volume and overdistending the remaining lung.     

Randomized controlled trial to improve adiposity, inflammation, and insulin resistance in obese African-American and Latino youth

The purpose of this study was to examine ethnic differences in the metabolic responses to a 16-week intervention designed to improve insulin sensitivity (SI), adiposity, and inflammation in obese African-American and Latino adolescents. A total of 100 participants (African Americans: n = 48, Latino: n = 52; age: 15.4 ± 1.1 years, BMI percentile: 97.3 ± 3.3) were randomly assigned to interventions: control (C; n = 30), nutrition (N; n = 39, 1×/week focused on decreasing sugar and increasing fiber intake), or nutrition + strength training (N+ST; n = 31, 2×/week). The following were measured at pre- and postintervention: strength, dietary intake, body composition (dual-energy X-ray absorptiometry/magnetic resonance imaging) and glucose/insulin indexes (oral glucose tolerance test (OGTT)/intravenous glucose tolerance test (IVGTT)) and inflammatory markers. Overall, N compared to C and N+ST reported significant improvements in SI (+16.5% vs. -32.3% vs. -6.9% respectively, P < 0.01) and disposition index (DI: +15.5% vs. -14.2% vs. -13.7% respectively, P < 0.01). N+ST compared to C and N reported significant reductions in hepatic fat fraction (HFF: -27.3% vs. -4.3% vs. 0% respectively, P < 0.01). Compared to N, N+ST reported reductions in plasminogen activator inhibitor-1 (PAI-1) (-38.3% vs. +1.0%, P < 0.01) and resistin (-18.7% vs. +11.3%, P = 0.02). There were no intervention effects for all other measures of adiposity or inflammation. Significant intervention by ethnicity interactions were found for African Americans in the N group who reported increases in total fat mass, 2-h glucose and glucose incremental areas under the curve (IAUC) compared to Latinos (P's < 0.05). These interventions yielded differential effects with N reporting favorable improvements in SI and DI and N+ST reporting marked reductions in HFF and inflammation. Both ethnic groups had significant improvements in metabolic health; however some improvements were not seen in African Americans.     

Effect of furosemide on hyperpnea-induced airway obstruction, injury, and microvascular leakage

Freed, Arthur N., Varsha Taskar, Brian Schofield, andChiharu Omori. Effect of furosemide on hyperpnea-induced airway obstruction, injury, and microvascular leakage. J. Appl. Physiol. 81(6): 2461-2467, 1996.Furosemideattenuates hyperpnea-induced airway obstruction (HIAO) in asthmaticsubjects via unknown mechanism(s). We studied the effect of furosemideon dry air-induced bronchoconstriction, mucosal injury, andbronchovascular hyperpermeability in a canine model of exercise-inducedasthma. Peripheral airway resistance (Rp) was recorded before and aftera 2-min dry-air challenge (DAC) at 2,000 ml/min. After pretreatmentwith aerosolized saline containing 0.75% dimethyl sulfoxide, DACincreased Rp 72 ± 11% (SE, n = 7) above baseline; aerosolized furosemide(10³ M) reduced thisresponse by ~50 ± 6% (P < 0.01). To assess bronchovascular permeability, colloidal carbon wasinjected (1 ml/kg iv) 1 min before DAC, and after 1 h, the vehicle- andfurosemide-treated airways were prepared for morphometric analysis.Light microscopy confirmed previous studies showing that DAC damagedthe airway epithelium and enhanced bronchovascular permeability.Furosemide did not inhibit dry air-induced mucosal injury orbronchovascular hyperpermeability and in fact tended to increase airwaydamage and vascular leakage. This positive trend toward enhancedbronchovascular permeability in DAC canine peripheral airways isconsistent with the hypothesis that furosemide inhibits HIAO in part byenhancing microvascular leakage and thus counterbalancing theevaporative water loss that occurs during hyperpnea.

     

Randomized controlled trial of chewing gum for weight loss

The possible effects on body weight of chewing gum on a regular schedule have not been tested in a randomized controlled trial (RCT). We conducted an 8-week RCT in 201 overweight and obese adults to test the hypothesis that receiving printed material on good nutrition and chewing gum for a minimum of 90 min/day (n = 102) would lead to greater weight loss than receiving printed nutrition information only (n = 99). Changes in BMI, waist circumference, and blood pressure were secondary outcomes. Adherence to the gum-chewing protocol in the intervention group was >95%. In the intention-to-treat analysis, there were virtually no changes in weight or BMI in either group between baseline and the end of the intervention at 8 weeks. Waist circumference decreased significantly in the intervention group between baseline and 8 weeks (mean ± SD change = -1.4 ± 5.3 cm; P = 0.0128); however, there was no significant difference in change in waist circumference comparing the groups. Similarly, systolic and diastolic blood pressure decreased significantly in the intervention group between baseline and 8 weeks (-3.0 ± 9.9 mm Hg; P = 0.0032 and -3.2 ± 7.3 mm Hg; P = 0.0001, respectively); however, there were no significant differences in the changes in systolic or diastolic blood pressure between the groups. Analyses including completers only produced essentially the same results. We conclude that chewing gum on a regular schedule for 8 weeks did not facilitate weight loss in these overweight and obese adults.     

beta blockade and intermittent claudication: placebo controlled trial of atenolol and nifedipine and their combination.

OBJECTIVE--To determine the effects of the beta 1 selective adrenoceptor blocker atenolol, the dihydropyridine calcium antagonist nifedipine, and the combination of atenolol plus nifedipine on objective and subjective measures of walking performance and foot temperature in patients with intermittent claudication. DESIGN--Randomised controlled double blind four way crossover trial. SETTING--Royal Hallamshire Hospital, Sheffield. SUBJECTS--49 patients (40 men) aged 39-70 with chronic stable intermittent claudication. INTERVENTIONS--Atenolol 50 mg twice daily; slow release nifedipine 20 mg twice daily; atenolol 50 mg plus slow release nifedipine 20 mg twice daily; placebo. Each treatment was given for four weeks with no washout interval between treatments. MAIN OUTCOME MEASURES--Claudication and walking distances on treadmill; skin temperature of feet as measured by thermistor and probe; blood pressure before and after exercise; subjective assessments of walking difficulty and foot coldness with visual analogue scales. RESULTS--Atenolol did not significantly alter claudication distance (mean change -6%; 95% confidence interval 1% to -13%), walking distance (-2%; 4% to -8%), or foot temperature. Nifedipine did not alter claudication distance (-4%; 3% to -11%), walking distance (-4%; 3% to -10%), or foot temperature. Atenolol plus nifedipine did not alter claudication distance but significantly reduced walking distance (-9%; -3% to -15% (p less than 0.003)) and skin temperature of the more affected foot (-1.1 degrees C; 0 to -2.2 degrees C (p = 0.05)). These effects on walking distance and foot temperature seemed unrelated to blood pressure changes. CONCLUSIONS--There was no evidence of adverse or beneficial effects of atenolol or nifedipine, when given singly, on peripheral vascular disease. The combined treatment, however, affected walking ability and foot temperature adversely. This may have been due to beta blockade plus reduced vascular resistance, which might also explain the reported adverse effects of pindolol and labetalol on claudication.     

The inhaled Rho kinase inhibitor Y-27632 protects against allergen-induced acute bronchoconstriction, airway hyperresponsiveness, and inflammation

Recently, we have shown that allergen-induced airway hyperresponsiveness (AHR) after the early (EAR) and late (LAR) asthmatic reaction in guinea pigs could be reversed acutely by inhalation of the Rho kinase inhibitor Y-27632. The present study addresses the effects of pretreatment with inhaled Y-27632 on the severity of the allergen-induced EAR and LAR, the development of AHR after these reactions, and airway inflammation. Using permanently instrumented and unrestrained ovalbumin (OA)-sensitized guinea pigs, single OA challenge-induced EAR and LAR, expressed as area under the lung function (pleural pressure, P(pl)) time-response curve, were measured, and histamine PC(100) (provocation concentration causing a 100% increase of P(pl)) values were assessed 24 h before, and at 6 and 24 h after, the OA challenge (after the EAR and LAR, respectively). Thirty minutes before and 8 h after OA challenge, saline or Y-27632 (5 mM) was nebulized. After the last PC(100) value, bronchoalveolar lavage (BAL) was performed, and the inflammatory cell profile was determined. It was demonstrated that inhalation of Y-27632 before allergen challenge markedly reduced the immediate allergen-induced peak rise in P(pl), without significantly reducing the overall EAR and LAR. Also, pretreatment with Y-27632 considerably protected against the development of AHR after the EAR and fully prevented AHR after the LAR. These effects could not be explained by a direct effect of Y-27632 on the histamine responsiveness, because of the short duration of the acute bronchoprotection of Y-27632 (<90 min). In addition, Y-27632 reduced the number of total inflammatory cells, eosinophils, macrophages, and neutrophils recovered from the BAL. Altogether, inhaled Y-27632 protects against acute allergen-induced bronchoconstriction, development of AHR after the EAR and LAR, and airway inflammation in an established guinea pig model of allergic asthma.     

Randomized controlled trial testing weight loss and abdominal obesity outcomes of moxibustion

Background

The purpose of this study was to investigate the efficacy of moxibustion therapy on weight loss, waist circumference and waist-to-hip ratio in young adult females. An experimental design, 51 Asian females were enrolled. Inclusion criteria included females with ages between 21 and 25 years-old and waist circumference?≥?80 cm, and the exclusion criteria included intolerance to moxibustion therapy and current illness. Two groups were formed, and the subjects in the experimental group received moxibustion sessions lasting 20 min and an educational video program for 30 min; however, participants in the control group received only the educational program every other week for 8 weeks. Dependent variable measurements (e.g., body weight, waist circumference and waist-to-hip ratio) were collected at baseline and follow-up for 8 weeks.

Results

Average body weight of the treatment group decreased significantly from ??1.478 kg (p?<?0.0001), while the average body weight in the control group did not decrease significantly ??0.038 kg (p?=?0.7197). Also, individuals in the moxibustion experimental group showed significant reductions (p?<?0.0001) in both waist circumference and waist-to-hip ratio.

Conclusion

Positive effects on anthropometry can be achieved by moxibustion intervention in conjunction with a weight loss education program. Especially waist circumference and waist-to-hip ratio had more clinically significant and more pronounced for health reasons Future studies can focus on the functional assessment of biomarkers associated with the immune system and relevant mechanisms of action.

     

Randomized controlled trial of a water-soluble formulation of lutein in humans

ABSTRACT

Lutein is poorly absorbed owing to their high hydrophobicity and crystallinity. This double-blind crossover trial involved eight healthy males who were administrated capsules containing either a lutein water-soluble formulation or a lutein oil suspension for 8 days. In the formulation group, plasma and erythrocytes lutein concentrations and baseline-corrected AUC were two-fold higher than those in the oil suspension group.     

Randomized controlled trial evaluating rapid pre-screen of cervical cytology specimens.

A randomized controlled trial of 75,355 cervical cytology specimens was performed comparing rapid pre-screen with no pre-screen. While the percentage of cases receiving a final report of definite high-grade abnormality was higher in the no pre-screen arm (no pre-screen = 0.70%, pre-screen = 0.65%), the percentage of cases receiving a final report of possible or definite high-grade abnormality was essentially identical in the two arms of the trial (no pre-screen = 1.22%, pre-screen = 1.21%). In the randomized trial, one extra cytology report of definite high-grade abnormality was made for every 12,568 slides pre-screened. This level of benefit was reduced by about half when rapid pre-screen was adopted as a routine laboratory practice.     

Fluticasone impact on airway dendritic cells in smokers: a randomized controlled trial

Background

Myeloid Dendritic cells are key drivers of inflammation in smoke-related lung diseases, whereas plasmacytoid DCs play a crucial role in the defense against infections. Effects of inhaled corticosteroids (ICS) on airway DCs in smokers are unknown.

Methods

In this randomized, double-blind, placebo-controlled clinical trial, 45 active cigarette smokers inhaled placebo, fluticasone or fluticasone plus salmeterol twice daily for 4 weeks. Bronchoalveolar lavage fluid DCs were analyzed using four-color flow cytometry before and after the inhalation period. In addition, fluticasone effects were tested on T-cell proliferation in co-cultures with blood myeloid DCs from smokers.

Results

Inhalation of fluticasone plus salmeterol, but not fluticasone alone or placebo, reduced endobronchial concentrations of myeloid DCs (median decrease: 24%), macrophages (median decrease: 26%) and neutrophils (median decrease: 76%). In contrast, fluticasone reduced plasmacytoid DC concentrations independently of salmeterol. There were no changes in the expression of function-associated surface molecules on myeloid DC (such as CD1a, Langerin, BDCA-1, CD83 or CCR5) in all groups after treatment. Fluticasone (either alone or in combination with salmeterol) suppressed T-cell proliferation in co-cultures with blood myeloid DCs from smokers.

Conclusions

Resistance to ICS monotherapy in smokers might in part be due to lacking effects on airway myeloid DCs, whereas the increased risk for infections during ICS therapy could be attributable to a reduction in plasmacytoid DCs. Combination therapy of fluticasone with salmeterol is associated with a reduction in airway myeloid DCs, but also airway macrophages and neutrophils.

Trial registration

Registered at ClinicalTrials.gov (identifier: {"type":"clinical-trial","attrs":{"text":"NCT00908362","term_id":"NCT00908362"}}NCT00908362) and the European Clinical Trial Database, EudraCT (identifier: 2009-009459-40).     

Peptidase modulation of noncholinergic vagal bronchoconstriction and airway microvascular leakage

We investigated whether inhibition of neutral endopeptidase 24.11 (NEP) and/or angiotensin-converting enzyme (ACE) modifies vagally induced nonadrenergic noncholinergic (NANC) airflow obstruction and airway microvascular leakage as measured by extravasation of Evans blue dye (intravenous) in anesthetized guinea pigs. We gave phosphoramidon to inhibit NEP and enalapril maleate or captopril to inhibit ACE. Animals pretreated with inhaled phosphoramidon (7.5 or 75 nmol), enalapril maleate (87 or 870 nmol), or captopril (350 nmol) reached higher peak lung resistance (RL) values (14.3 +/- 2.7, 15.7 +/- 3.8, 16.7 +/- 3.8, 11.4 +/- 1.6, and 24.6 +/- 3.5 cmH2O.ml-1.s, respectively) than saline-treated animals (5.9 +/- 1.1; P less than 0.05) after bilateral vagus nerve stimulation (5 Hz, 10 V, 10 ms, 150 s). Intravenous phosphoramidon (1 mg/kg), but not intravenous captopril (6 mg/kg), potentiated peak RL (22.9 +/- 6.9 and 7.1 +/- 1.5 cmH2O.ml-1.s, respectively). Vagal nerve stimulation (1 and 5 Hz) increased the extravasation of Evans blue dye in tracheobronchial tissues compared with sham-stimulated animals, but this was not potentiated by inhaled enzyme inhibitors or intravenous captopril. However, intravenous phosphoramidon significantly augmented the extravasation of Evans blue dye in main bronchi and intrapulmonary airways. We conclude that degradative enzymes regulate both NANC-induced airflow obstruction and airway microvascular leakage.     

Randomized, controlled trial of therapy interruption in chronic HIV-1 infection

Background

Approaches to limiting exposure to antiretroviral therapy (ART) drugs are an active area of HIV therapy research. Here we present longitudinal follow-up of a randomized, open-label, single-center study of the immune, viral, and safety outcomes of structured therapy interruptions (TIs) in patients with chronically suppressed HIV-1 infection as compared to equal follow-up of patients on continuous therapy and including a final therapy interruption in both arms.

Methods and Findings

Forty-two chronically HIV-infected patients on suppressive ART with CD4 counts higher than 400 were randomized 1:1 to either (1) three successive fixed TIs of 2, 4, and 6 wk, with intervening resumption of therapy with resuppression for 4 wk before subsequent interruption, or (2) 40 wk of continuous therapy, with a final open-ended TI in both treatment groups. Main outcome was analysis of the time to viral rebound (>5,000 copies/ml) during the open-ended TI. Secondary outcomes included study-defined safety criteria, viral resistance, therapy failure, and retention of immune reconstitution.There was no difference between the groups in time to viral rebound during the open-ended TI (continuous therapy/single TI, median [interquartile range] = 4 [1–8] wk, n = 21; repeated TI, median [interquartile range] = 5 [4–8] wk, n = 21; p = 0.36). No differences in study-related adverse events, viral set point at 12 or 20 wk of open-ended interruption, viral resistance or therapy failure, retention of CD4 T cell numbers on ART, or retention of lymphoproliferative recall antigen responses were noted between groups. Importantly, resistance detected shortly after initial viremia following the open-ended TI did not result in a lack of resuppression to less than 50 copies/ml after reinitiation of the same drug regimen.

Conclusion

Cycles of 2- to 6-wk time-fixed TIs in patients with suppressed HIV infection failed to confer a clinically significant benefit with regard to viral suppression off ART. Also, secondary analysis showed no difference between the two strategies in terms of safety, retention of immune reconstitution, and clinical therapy failure. Based on these findings, we suggest that further clinical research on the long-term consequences of TI strategies to decrease drug exposure is warranted.     

Effect of monensin, fish oil or their combination on in vitro fermentation and conjugated linoleic acid (CLA) production by ruminal bacteria

An in vitro study was conducted to examine the effect of adding monensin, fish oil, or their combination on rumen fermentation and conjugated linoleic acid (CLA) production by mixed ruminal bacteria when incubated with safflower oil. Concentrate (1 g/100 ml) with safflower oil (0.2 g/100 ml) was added to a mixed solution (600 ml) of strained rumen fluid and buffer (control). Monensin (10 ppm), fish oil (0.02 g/100 ml), or monensin plus fish oil was also added into control mixture. All the culture solutions prepared were incubated anaerobically at 39 °C for 12 h. A higher pH and ammonia concentration were observed from the culture solution containing monensin at 12 h of incubation than those from the control or the culture containing fish oil. Monensin increased (P < 0.007) the C₃ content over all the collection times of culture solution while reducing the C₄ content at 6 h (P < 0.018) and 12 h (P < 0.001) of incubations. Supplementation of monensin, fish oil or their combination changed the content of C₁₈-fatty acids of ruminal culture. Monensin alone reduced (P < 0.021) the content of cis-9, trans-11 CLA compared to fish oil at all sampling times, but increased (P < 0.041) the trans-10, cis-12 CLA production compared to fish oil addition and the control which were similar at incubation for 12 h. The combination of monensin and fish oil increased the content of cis-9, trans-11 CLA (P < 0.023) and transvaccenic acid (TVA, P < 0.018) significantly compared to the control or monensin alone at incubation for 12 h.     

Randomised double-blind placebo-controlled trial of fish oil in the treatment of depression

Converging evidence suggests that omega-3 polyunsaturated fatty acids have aetiological importance in depression. To determine the effect of adding fish oil to existing therapy in participants who were being treated for depression in a community setting, 77 participants were randomly assigned to receive 8 g of either fish or olive oil per day in addition to their existing therapy. Fifty-nine (77%) participants completed 12 weeks of treatment. Dietary, biochemical and lifestyle factors were measured throughout the study. Mood was assessed using the Short Form Hamilton Depression Rating Scale (HDRS-SF) and the Beck Depression Inventory II. Sample size calculations were based on the HDRS-SF. Intention-to-treat and per protocol analyses were carried out using residual maximum likelihood. There was no evidence that fish oil improved mood when compared to the placebo oil, despite an increase in circulating omega-3 polyunsaturated fatty acids. However, mood improved significantly in both groups within the first 2 weeks of the study (P<0.001) and this improvement was sustained throughout. In conclusion, fish oil was no more effective than the control as an add-on therapy for depression in this setting.