The performance of the SD BIOLINE Dengue DUO? rapid immunochromatographic test kit for the detection of NS1 antigen,IgM and IgG antibodies during a dengue type 1 epidemic in Jamaica

Background

Dengue is an important mosquito-borne viral infection that affects millions of persons worldwide. Early diagnosis is necessary to effect appropriate management and decrease mortality. Immunochromatographic tests are advantageous in producing dengue test results within 30 min but these results should be sensitive and specific. In this study we evaluated the diagnostic performance of the SD BIOLINE Dengue DUO® rapid immunochromatographic test kit. A panel of 309 dengue and 30 non-dengue single serum samples characterized by using reference enzyme-linked immunosorbent assays (ELISAs) was used. These samples were received in the virology laboratory for routine testing during a dengue type 1 outbreak between October to December, 2012.

Results

The overall diagnostic sensitivities of the SD BIOLINE Dengue DUO® rapid testfor IgM, IgG and NSI were 49.3 % (95 % CI: 41.3-57.4), 39.1 % (95 % CI: 33.3-45.2) and 90 % (95 % CI: 82.1-94.7), respectively. The IgM and IgG detection rates were significantly lower than that of the NSI (p < 0.001). However the combination of the IgM detection with NS1 detection or both NS1 and IgG resulted in a significant (p < 0.001) increase in sensitivity to 97.5 % (95 % CI: 92.9-99.2) and 98.9 % (95 % CI: 96.0-99.7), respectively. These higher sensitivities were achieved without any decrease in specificities.

Conclusions

This study revealed that combining two or more parameters of the SD BIOLINE Dengue DUO® rapid kit significantly improved the sensitivity of diagnosis of dengue virus infection and supports its usefulness in the Jamaican setting.     

Computer quantification of airway collapse on forced expiration to predict the presence of emphysema

Background

Spirometric parameters are the mainstay for diagnosis of COPD, but cannot distinguish airway obstruction from emphysema. We aimed to develop a computer model that quantifies airway collapse on forced expiratory flow–volume loops. We then explored and validated the relationship of airway collapse with computed tomography (CT) diagnosed emphysema in two large independent cohorts.

Methods

A computer model was developed in 513 Caucasian individuals with ≥15 pack-years who performed spirometry, diffusion capacity and CT scans to quantify emphysema presence. The model computed the two best fitting regression lines on the expiratory phase of the flow-volume loop and calculated the angle between them. The collapse was expressed as an Angle of collapse (AC) which was then correlated with the presence of emphysema. Findings were validated in an independent group of 340 individuals.

Results

AC in emphysema subjects (N = 251) was significantly lower (131° ± 14°) compared to AC in subjects without emphysema (N = 223), (152° ± 10°) (p < 0.0001). Multivariate regression analysis revealed AC as best indicator of visually scored emphysema (R² = 0.505, p < 0.0001) with little significant contribution of K_CO, %predicted and FEV_1, %predicted to the total model (total R² = 0.626, p < 0.0001). Similar associations were obtained when using CT-automated density scores for emphysema assessment. Receiver operating characteristic (ROC) curves pointed to 131° as the best cut-off for emphysema (95.5% positive predictive value, 97% specificity and 51% sensitivity). Validation in a second group confirmed the significant difference in mean AC between emphysema and non-emphysema subjects. When applying the 131° cut-off, a positive predictive value of 95.6%, a specificity of 96% and a sensitivity of 59% were demonstrated.

Conclusions

Airway collapse on forced expiration quantified by a computer model correlates with emphysema. An AC below 131° can be considered as a specific cut-off for predicting the presence of emphysema in heavy smokers.     

Severe and uncontrolled adult asthma is associated with vitamin D insufficiency and deficiency

Background

Vitamin D has effects on the innate and adaptive immune system. In asthmatic children low vitamin D levels are associated with poor asthma control, reduced lung function, increased medication intake, and exacerbations. Little is known about vitamin D in adult asthma patients or its association with asthma severity and control.

Methods

Clinical parameters of asthma control and 25-hydroxyvitamin D (25(OH)D) serum concentrations were evaluated in 280 adult asthma patients (mean ± SD: 45.0 ± 13.8 yrs., 40% male, FEV1 74.9 ± 23.4%, 55% severe, 51% uncontrolled).

Results

25(OH)D concentrations in adult asthmatics were low (25.6 ±11.8 ng/ml) and vitamin D insufficiency or deficiency (vitamin D <30 ng/ml) was common (67%). 25(OH)D levels were related to asthma severity (intermittent: 31.1 ± 13.0 ng/ml, mild: 27.3 ± 11.9 ng/ml, moderate: 26.5 ± 12.0 ng/ml, severe: 24.0 ± 11.8 ng/ml, p = 0.046) and control (controlled: 29.5 ± 12.5 ng/ml, partly controlled 25.9 ± 10.8 ng/ml, uncontrolled: 24.2 ± 11.8 ng/ml, p = 0.030). The frequency of vitamin D insufficiency or deficiency was significantly higher in patients with severe or uncontrolled asthma and was associated with a lower FEV1 (vitamin D <30 vs. ≥30 ng/ml 2.3 ± 0.9 L vs. 2.7 ± 1.0 L, p = 0.006), higher levels of exhaled NO (45 ± 46 ppb vs. 31 ± 37 ppb, p = 0.023), a higher BMI (28.3 ± 6.2 vs. 25.1 ± 3.9, p < 0.001), and sputum eosinophilia (5.1 ± 11.8% vs. 0.5 ± 1.0%, p = 0.005). The use of oral corticosteroids or sputum eosinophilia was associated with a 20% or 40% higher risk of vitamin D insufficiency or deficiency.

Conclusions

25(OH)D levels below 30 ng/ml are common in adult asthma and most pronounced in patients with severe and/or uncontrolled asthma, supporting the hypothesis that improving suboptimal vitamin D status might be effective in prevention and treatment of asthma.     

Leptin modulates electrophysiological characteristics and isoproterenol-induced arrhythmogenesis in atrial myocytes

Background

Obesity is an important risk factor for atrial fibrillation (AF). Leptin is an important adipokine. However, it is not clear whether leptin directly modulates the electrophysiological characteristics of atrial myocytes.

Results

Whole cell patch clamp and indo-1 fluorescence were used to record the action potentials (APs) and ionic currents in isolated rabbit left atrial (LA) myocytes incubated with and without (control) leptin (100 nM) for 1 h to investigate the role of leptin on atrial electrophysiology. Leptin-treated LA myocytes (n = 19) had longer 20% of AP duration (28 ± 3 vs. 21 ± 2 ms, p < 0.05), but similar 50% of AP duration (51 ± 4 vs. 50 ± 3 ms, p > 0.05), and 90% of AP duration (89 ± 5 vs. 94 ± 4 ms, p > 0.05), as compared to the control (n = 22). In the presence of isoproterenol (10 nM), leptin-treated LA myocytes (n = 21) showed a lower incidence (19% vs. 54.2%, p < 0.05) of delayed afterdepolarization (DAD) than the control (n = 24). Leptin-treated LA myocytes showed a larger sodium current, but a smaller ultra-rapid delayed rectifier potassium current, and sodium-calcium exchanger current than the control. Leptin-treated and control LA myocytes exhibited a similar late sodium current, inward rectifier potassium current, transient outward current and L-type calcium current. In addition, the leptin-treated LA myocytes (n = 38) exhibited a smaller intracellular Ca²⁺ transient (0.21 ± 0.01 vs. 0.26 ± 0.01 R410/485, p < 0.05) and sarcoplasmic reticulum Ca²⁺ content (0.35 ± 0.02 vs. 0.43 ± 0.03 R410/485, p < 0.05) than the control LA myocytes (n = 42).

Conclusions

Leptin regulates the LA electrophysiological characteristics and attenuates isoproterenol-induced arrhythmogenesis.     

In vivo analgesic,antipyretic, and anti-inflammatory potential in Swiss albino mice and in vitro thrombolytic activity of hydroalcoholic extract from Litsea glutinosa leaves

Background

The study was conducted to evaluate the in vitro thrombolytic activity, and in vivo analgesic, anti-inflammatory and antipyretic potentials of different hydrocarbon soluble extracts of Litsea glutinosa leaves for the first time widely used in the folkloric treatments in Bangladesh. This work aimed to create new insights on the fundamental mechanisms of the plant extracts involved in these activities.

Results

In thrombolytic activity assay, a significant clot disruption was observed at dose of 1 mg/mL for each of the extracts (volume 100 μL) when compared to the standard drug streptokinase. The n-hexane, ethyl acetate, chloroform, and crude methanolic extracts showed 32.23 ± 0.26, 37.67 ± 1.31, 43.13 ± 0.85, and 46.78 ± 0.9% clot lysis, respectively, whereas the positive control streptokinase showed 93.35 ± 0.35% disruption at the dose of 30,000 I.U. In hot plate method, the highest pain inhibitory activity was found at a dose of 500 mg/kg of crude extract (15.54 ± 0.37 sec) which differed significantly (P <0.01 and P <0.001) with that of the standard drug ketorolac (16.38 ± 0.27 sec). In acetic acid induced writhing test, the crude methanolic extract showed significant (P <0.01 and P <0.001) analgesic potential at doses 250 and 500 mg/kg body weight (45.98 and 56.32% inhibition, respectively), where ketorolac showed 64.36% inhibition. In anti-inflammatory activity test, the crude methanolic extract showed significant (P <0.001) potential at doses 250 and 500 mg/kg body weight (1.51 ± 0.04 and 1.47 ± 0.03 mm paw edema, respectively), where ketorolac showed 1.64 ± 0.05 mm edema after 3 h of carrageenan injection. In antipyretic activity assay, the crude extract showed notable reduction in body temperature (32.78 ± 0.46°C) at dose of 500 mg/kg-body weight, when the standard (at dose 150 mg/kg-body weight) exerted 33.32 ± 0.67°C temperature after 3 h of administration.

Conclusions

Our results yield that the crude hydroalcoholic extract has better effects than the other in all trials. In the context, it can be said that the leaves of L. glutinosa possess remarkable pharmacological effects, and justify its traditional use as analgesic, antipyretic, anti-inflammatory, and thrombolytic agent.     

TNF-α is associated with loss of lean body mass only in already cachectic COPD patients

Background

Systemic inflammation may contribute to cachexia in patients with chronic obstructive pulmonary disease (COPD). In this longitudinal study we assessed the association between circulating C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 levels and subsequent loss of fat free mass and fat mass in more than 400 COPD patients over three years.

Methods

The patients, aged 40–76, GOLD stage II-IV, were enrolled in 2006/07, and followed annually. Fat free mass and fat mass indexes (FFMI & FMI) were calculated using bioelectrical impedance, and CRP, TNF-α, IL-1ß, and IL-6 were measured using enzyme immunoassays. Associations with mean change in FFMI and FMI of the four inflammatory plasma markers, sex, age, smoking, FEV₁, inhaled steroids, arterial hypoxemia, and Charlson comorbidity score were analyzed with linear mixed models.

Results

At baseline, only CRP was significantly (but weakly) associated with FFMI (r = 0.18, p < 0.01) and FMI (r = 0.27, p < 0.01). Univariately, higher age, lower FEV₁, and use of beta2-agonists were the only significant predictors of decline in FFMI, whereas smoking, hypoxemia, Charlson score, and use of inhaled steroids predicted increased loss in FMI. Multivariately, high levels of TNF-α (but not CRP, IL-1ß or IL-6) significantly predicted loss of FFMI, however only in patients with established cachexia at entry.

Conclusion

This study does not support the hypothesis that systemic inflammation is the cause of accelerated loss of fat free mass in COPD patients, but suggests a role for TNF-α in already cachectic COPD patients.     

Capillary pCO2 helps distinguishing idiopathic pulmonary arterial hypertension from pulmonary hypertension due to heart failure with preserved ejection fraction

Rationale

The demographics of patients with idiopathic pulmonary arterial hypertension (IPAH) are changing and this diagnosis is increasingly being made in older patients. However, diagnostic misclassifications are common as it may be difficult to differentiate between IPAH and pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF). We investigated the hypothesis that the capillary pCO₂ (p_cCO₂) may help distinguishing between idiopathic pulmonary arterial hypertension (IPAH) and pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF).

Methods

In a cross-sectional study, we retrospectively assessed p_cCO₂ levels (obtained from arterialized capillary blood at the time of diagnosis) from patients with IPAH or PH-HFpEF, respectively. Receiver operated characteristics (ROC) were used to determine the p_cCO₂ level providing the best discrimination between these two conditions. P_cCO₂ values were considered helpful if they were associated with a negative predictive value >0.9 to excluded either IPAH or PH-HFpEF.

Results

The study enrolled 185 patients, 99 with IPAH (74% female; age 47 ± 17 years; body mass index 26 ± 5 kg/m², PAPm 53 ± 12 mmHg, PAWP 8 ± 3 mmHg), and 86 with PH-HFpEF (64% female; age 69 ± 10 years; body mass index 30 ± 6 kg/m², PAPm 47 ± 10 mmHg, PAWP 21 ± 5 mmHg). P_cCO₂ at time of diagnosis was 33 ± 4 mmHg in the IPAH group and 40 ± 5 mmHg in the PH-HFpEF group (p < 0.001), respectively. According to ROC analysis, a p_cCO₂ of 36 mmHg was the best discriminator between both entities with an area under curve of 0.87 (p < 0.001). The likelihood of PH-HFpEF was <10% in patients with a P_cCO₂ < 34 mmHg, whereas the likelihood of IPAH was <10% in patients with a P_cCO₂ > 41 mmHg.

Conclusions

P_cCO₂ levels were significantly lower in IPAH compared to PH-HFpEF and may provide useful information in differentiating between both conditions.     

Remission in rheumatoid arthritis: benefit over low disease activity in patient-reported outcomes and costs

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes a considerable burden for the patient and society. It is not clear yet whether aiming for remission (REM) is worthwhile, especially when compared with low disease activity (LDA).

Methods

In 356 consecutive RA patients, we obtained data on physical function (health assessment questionnaire (HAQ)), health-related quality of life (HRQoL: Short Form 36 (SF36), Short Form 6 dimensions (SF-6D), Euro QoL 5D (EQ-5D)), work productivity (work productivity and activity impairment questionnaire (WPAI)), as well as estimation of direct and indirect costs. Cross-sectionally, data were compared in patients within different levels of disease activity according to the simplified disease activity index (SDAI; remission (REM ≤3.3); n = 87; low disease activity (LDA: 3.3 < SDAI ≤11); n = 103; moderate to high disease activity (MDA/HDA) >11 n = 119) by using analyses of variance (ANOVA). Longitudinal investigations assessed patients who changed from LDA to REM and vice versa.

Results

We found differences in patients achieving REM compared with LDA for HAQ (0.39 ± 0.58 versus 0.72 ± 68), WPAI (percentage impairment while working 11.8% ± 18.7% versus 26.8% ± 23.9%; percentage of overall activity impairment, 10.8% ± 14.1% versus 29.0% ± 23.6%)), EQ-5D (0.89 ± 0.12 versus 0.78 ± 0.6) and SF-36 (physical component score (PCS): 46.0 ± 8.6 versus 38.3 ± 10.5; mental component score (MCS): 49.9 ± 11.1 versus 47.9 ± 12.3) (P < 0.01 for all, except for SF36 MCS). Regarding costs, we found significant differences of direct and indirect costs (P < 0.05) within different levels of disease activity, with higher costs in patients with higher states of disease activity. Longitudinal evaluations confirmed the main analyses.

Conclusion

Patients with REM show better function, HRQoL, and productivity, even when compared with another good state, such as LDA. Also from a cost perspective, REM appears superior to all other states.     

The effects of salbutamol on epithelial ion channels depend on the etiology of acute respiratory distress syndrome but not the route of administration

Introduction

We investigated the effects of intravenous and intratracheal administration of salbutamol on lung morphology and function, expression of ion channels, aquaporin, and markers of inflammation, apoptosis, and alveolar epithelial/endothelial cell damage in experimental pulmonary (p) and extrapulmonary (exp) mild acute respiratory distress syndrome (ARDS).

Methods

In this prospective randomized controlled experimental study, 56 male Wistar rats were randomly assigned to mild ARDS induced by either intratracheal (n = 28, ARDSp) or intraperitoneal (n = 28, ARDSexp) administration of E. coli lipopolysaccharide. Four animals with no lung injury served as controls (NI). After 24 hours, animals were anesthetized, mechanically ventilated in pressure-controlled mode with low tidal volume (6 mL/kg), and randomly assigned to receive salbutamol (SALB) or saline 0.9% (CTRL), intravenously (i.v., 10 μg/kg/h) or intratracheally (bolus, 25 μg). Salbutamol doses were targeted at an increase of ≈ 20% in heart rate. Hemodynamics, lung mechanics, and arterial blood gases were measured before and after (at 30 and 60 min) salbutamol administration. At the end of the experiment, lungs were extracted for analysis of lung histology and molecular biology analysis. Values are expressed as mean ± standard deviation, and fold changes relative to NI, CTRL vs. SALB.

Results

The gene expression of ion channels and aquaporin was increased in mild ARDSp, but not ARDSexp. In ARDSp, intravenous salbutamol resulted in higher gene expression of alveolar epithelial sodium channel (0.20 ± 0.07 vs. 0.68 ± 0.24, p < 0.001), aquaporin-1 (0.44 ± 0.09 vs. 0.96 ± 0.12, p < 0.001) aquaporin-3 (0.31 ± 0.12 vs. 0.93 ± 0.20, p < 0.001), and Na-K-ATPase-α (0.39 ± 0.08 vs. 0.92 ± 0.12, p < 0.001), whereas intratracheal salbutamol increased the gene expression of aquaporin-1 (0.46 ± 0.11 vs. 0.92 ± 0.06, p < 0.001) and Na-K-ATPase-α (0.32 ± 0.07 vs. 0.58 ± 0.15, p < 0.001). In ARDSexp, the gene expression of ion channels and aquaporin was not influenced by salbutamol. Morphological and functional variables and edema formation were not affected by salbutamol in any of the ARDS groups, regardless of the route of administration.

Conclusion

Salbutamol administration increased the expression of alveolar epithelial ion channels and aquaporin in mild ARDSp, but not ARDSexp, with no effects on lung morphology and function or edema formation. These results may contribute to explain the negative effects of β2-agonists on clinical outcome in ARDS.     

Discriminating Malaria from Dengue Fever in Endemic Areas: Clinical and Biological Criteria,Prognostic Score and Utility of the C-Reactive Protein: A Retrospective Matched-Pair Study in French Guiana

Background

Dengue and malaria are two major public health concerns in tropical settings. Although the pathogeneses of these two arthropod-borne diseases differ, their clinical and biological presentations are unspecific. During dengue epidemics, several hundred patients with fever and diffuse pain are weekly admitted at the emergency room. It is difficult to discriminate them from patients presenting malaria attacks. Furthermore, it may be impossible to provide a parasitological microscopic examination for all patients. This study aimed to establish a diagnostic algorithm for communities where dengue fever and malaria occur at some frequency in adults.

Methodology/Principal Findings

A sub-study using the control groups of a case-control study in French Guiana – originally designed to compare dengue and malaria co-infected cases to single infected cases – was performed between 2004 and 2010. In brief, 208 patients with malaria matched to 208 patients with dengue fever were compared in the present study. A predictive score of malaria versus dengue was established using .632 bootstrap procedures. Multivariate analysis showed that male gender, age, tachycardia, anemia, thrombocytopenia, and CRP>5 mg/l were independently associated with malaria. The predictive score using those variables had an AUC of 0.86 (95%CI: 0.82–0.89), and the CRP was the preponderant predictive factor. The sensitivity and specificity of CRP>5 mg/L to discriminate malaria from dengue were of 0.995 (95%CI: 0.991–1) and 0.35 (95%CI 0.32–0.39), respectively.

Conclusions/Significance

The clinical and biological score performed relatively well for discriminating cases of dengue versus malaria. Moreover, using only the CRP level turned to be a useful biomarker to discriminate feverish patients at low risk of malaria in an area where both infections exist. It would avoid more than 33% of unnecessary parasitological examinations with a very low risk of missing a malaria attack.     

Biochemical and haematological changes in HIV subjects receiving winniecure antiretroviral drug in Nigeria

Background

Hematological and biochemical abnormalities are among the most common clinicopathological manifestations of HIV patients on ART. Consequently, the development and assessment of indigenous antiretroviral drugs with minimal abnormalities becomes a necessity. The objective of this investigation was to assess potential haematological and biochemical abnormalities that may be associated with the administration of Winniecure ART in HIV patients undergoing treatment in Nigeria. Fifty (50) confirmed HIV positive ART naïve patients aged 36 ± 10 were observed for haematological and biochemical responses for 12 weeks. Haematological responses were assessed thrice at 6 weeks interval using coulter Ac-T differential analyser and biochemical indicators (bilirubin, creatine, urea, amylase, ALT, ALP, AST, albumin) assayed spectrophotometrically.

Results

The biochemical parameters ALP (P < 0.05), ALT (P < 0.0001), AST (P < 0.001) and amylase (P < 0.05) slightly increased at the 12^th week, no significant change was observed in plasma creatinine and urea concentrations while albumin levels decreased non-significantly (P > 0.002). Haematological results showed consistent reduction of ESR, eosinophil, absolute and differential lymphocytes, granulocytes and total WBC in the test subjects throughout the assessment period. Conversely, haemoglobin, platelet and PCV increased significantly (P < 0.05). At the 12^th week thrombocytopenia (10.30%) and anaemia (76%) were reduced to 2% and 31% respectively while neutropenia (4.2 to 8%), leucopenia (26.8 to 30%) and lymphopenia (1 to 10%) increased. No cases of neutrophilia, lymphocytosis, eosinophilia and leukocytosis was observed.

Conclusion

The drug has a reduced haematological abnormalities and normal kidney function was unaffected though there were signs of possible abnormal levels of hepatic enzymes beyond 12 weeks of treatment.     

Rivaroxaban modulates electrical and mechanical characteristics of left atrium

Background

Rivaroxaban reduces stroke in patients with atrial fibrillation (AF). Left atrium (LA) plays a critical role in the pathophysiology of AF. However, the electromechanical effects of rivaroxaban on LA are not clear.

Results

Conventional microelectrodes and a whole-cell patch-clamp were used to record the action potentials (APs) and ionic currents in rabbit LA preparations and isolated single LA cardiomyocytes before and after the administration of rivaroxaban. Rivaroxaban (10, 30, 100, and 300 nM) concentration-dependently reduced LA (n = 7) AP durations at 90% repolarization (APD₉₀) from 76 ± 2 to 79 ± 3, 67 ± 4 (P < 0.05, vs. control), 59 ± 5, (P < 0.01, vs. control), and 56 ± 4 ms (P < 0.005, vs. control), respectively. Rivaroxaban (10, 30, 100, and 300 nM) concentration-dependently increased the LA (n = 7) diastolic tension by 351 ± 69 (P < 0.05, vs. control), 563 ± 136 (P < 0.05, vs. control), 582 ± 119 (P < 0.05, vs. control), and 603 ± 108 mg (P < 0.005, vs. control), respectively, but did not change LA contractility. In the presence of L-NAME (100 μM) and indomethacin (10 μM), additional rivaroxaban (300 nM) treatment did not significantly further increase the LA (n = 7) diastolic tension, but shortened the APD₉₀ from 73 ± 2 to 60 ± 6 ms (P < 0.05, vs. control). Rivaroxaban (100 nM) increased the L-type calcium current and ultra-rapid delayed rectifier potassium current, but did not change the transient outward potassium current in isolated LA cardiomyocytes.

Conclusions

Rivaroxaban modulates LA electrical and mechanical characteristics with direct ionic current effects.     

Increased plasma mannose binding lectin levels are associated with bronchiolitis obliterans after lung transplantation

Background

Long-term lung allograft survival is limited by bronchiolitis obliterans syndrome (BOS). Mannose binding lectin (MBL) belongs to the innate immune system, participates in complement activation, and may predispose to graft rejection. We investigated mannose binding (MBL) during cold ischemia and in tissue samples from explanted lungs with BOS, and assessed MBL and complement proteins in plasma post-lung transplantation relative to BOS staging.

Methods

MBL was detected by immunohistochemistry lung tissue at the time of cold ischemia and in samples with BOS. MBL was assayed in the peripheral blood of 66 lung transplant patients transplanted between 1990–2007.

Results

MBL localized to vasculature and basement membrane during cold ischemia and BOS. Patients further out post-lung transplant > 5 years (n = 33), had significantly lower levels of MBL in the blood compared to lung transplant patients < 5 years with BOS Op-3 (n = 17), 1738 ± 250 ng/ml vs 3198 ± 370 ng/ml, p = 0.027, and similar levels to lung transplant patients < 5 years with BOS 0 (n = 16), 1738 ± 250 ng/ml vs 1808 ± 345 ng/ml. MBL levels in all BOS 0 (n = 30) vs. all BOS Op-3 (n = 36) were 1378 ± 275 ng/ml vs. 2578 ± 390 ng/ml, p = 0.001, respectively. C3 plasma levels in BOS 0 (n = 30) vs. BOS Op-3 (n = 36) were 101 ± 19.8 mg/ml vs. 114 ± 25.2 mg/ml, p = 0.024, respectively.

Conclusions

MBL localizes within the lung during graft ischemia and BOS, higher levels of plasma MBL are associated with BOS Op-3 and < 5 years post-transplant, and higher level of plasma complement protein C3 was associated with BOS Op-3 clinical status. MBL may serve as a biomarker for poorer outcome post-lung transplantation.     

Small airway dysfunction is associated to excessive bronchoconstriction in asthmatic patients

Background

We investigated whether a relationship between small airways dysfunction and bronchial hyperresponsiveness (BHR), expressed both in terms of ease of airway narrowing and of excessive bronchoconstriction, could be demonstrated in asthma.

Methods

63 (36 F; mean age 42 yr ± 14) stable, mild-to-moderate asthmatic patients (FEV₁ 92% pred ±14; FEV₁/FVC 75% ± 8) underwent the methacholine challenge test (MCT). The degree of BHR was expressed as PD₂₀ (in μg) and as ∆FVC%. Peripheral airway resistance was measured pre- and post-MCT by impulse oscillometry system (IOS) and expressed as R5-R20 (in kPa sL⁻¹).

Results

All patients showed BHR to methacholine (PD₂₀ < 1600 μg) with a PD₂₀ geometric (95% CI) mean value of 181(132–249) μg and a ∆FVC% mean value of 13.6% ± 5.1, ranging 2.5 to 29.5%. 30 out of 63 patients had R5-R20 > 0.03 kPa sL⁻¹ (>upper normal limit) and showed ∆FVC%, but not PD₂₀ values significantly different from the 33 patients who had R5-R20 ≤ 0.03 kPa sL⁻¹ (15.8% ± 4.6 vs 11.5% ± 4.8, p < 0.01 and 156(96–254) μg vs 207 (134–322) μg, p = 0.382). In addition, ∆FVC% values were significantly related to the corresponding pre- (r = 0.451, p < 0.001) and post-MCT (r = 0.376, p < 0.01) R5-R20 values.

Conclusions

Our results show that in asthmatic patients, small airway dysfunction, as assessed by IOS, is strictly associated to BHR, expressed as excessive bronchoconstriction, but not as ease of airway narrowing.     

Acquired defects in CFTR-dependent β-adrenergic sweat secretion in chronic obstructive pulmonary disease

Rationale

Smoking-induced chronic obstructive pulmonary disease (COPD) is associated with acquired systemic cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. Recently, sweat evaporimetry has been shown to efficiently measure β-adrenergic sweat rate and specifically quantify CFTR function in the secretory coil of the sweat gland.

Objectives

To evaluate the presence and severity of systemic CFTR dysfunction in smoking-related lung disease using sweat evaporimetry to determine CFTR-dependent sweat rate.

Methods

We recruited a cohort of patients consisting of healthy never smokers (N = 18), healthy smokers (12), COPD smokers (25), and COPD former smokers (12) and measured β-adrenergic sweat secretion rate with evaporative water loss, sweat chloride, and clinical data (spirometry and symptom questionnaires).

Measurements and main results

β-adrenergic sweat rate was reduced in COPD smokers (41.9 ± 3.4, P < 0.05, ± SEM) and COPD former smokers (39.0 ± 5.4, P < 0.05) compared to healthy controls (53.6 ± 3.4). Similarly, sweat chloride was significantly greater in COPD smokers (32.8 ± 3.3, P < 0.01) and COPD former smokers (37.8 ± 6.0, P < 0.01) vs. healthy controls (19.1 ± 2.5). Univariate analysis revealed a significant association between β-adrenergic sweat rate and female gender (β = 0.26), age (−0.28), FEV₁% (0.35), dyspnea (−0.3), and history of smoking (−0.27; each P < 0.05). Stepwise multivariate regression included gender (0.39) and COPD (−0.43) in the final model (R² = 0.266, P < 0.0001).

Conclusions

β-adrenergic sweat rate was significantly reduced in COPD patients, regardless of smoking status, reflecting acquired CFTR dysfunction and abnormal gland secretion in the skin that can persist despite smoking cessation. β-adrenergic sweat rate and sweat chloride are associated with COPD severity and clinical symptoms, supporting the hypothesis that CFTR decrements have a causative role in COPD pathogenesis.     

A pilot crossover study: effects of an intervention using an activity monitor with computerized game functions on physical activity and body composition

Background

Wearing an activity monitor as a motivational tool and incorporating a behavior-based reward system or a computerized game element might have a synergistic effect on an increase in daily physical activity, thereby inducing body fat reduction. This pilot crossover study aimed to examine the effects of a short-term lifestyle intervention using an activity monitor with computerized game functions on physical activity and body composition.

Methods

Twenty healthy volunteers (31 ± 3 years) participated in a 12-week crossover study. The participants were randomly assigned to either Group A (a 6-week game intervention followed by a 6-week normal intervention) or Group B (a 6-week normal intervention followed by a 6-week game intervention). The participants wore both a normal activity monitor (Lifecorder EX) and an activity monitor with computerized game functions (Yuuhokei) during the game intervention, whereas they only wore a normal activity monitor during the normal intervention. Before, during, and after the intervention, body composition was assessed.

Results

Significantly more daily steps were recorded for the game intervention than for the normal intervention (10,520 ± 562 versus 8,711 ± 523 steps/day, P < 0.01). The participants performed significantly more physical activity at an intensity of ≥ 3 metabolic equivalents (METs) in the game intervention than in the normal intervention (3.1 ± 0.2 versus 2.4 ± 0.2 METs · hour/day, P < 0.01). Although body mass and fat were significantly reduced in both periods (P < 0.01), the difference in body fat reduction was significantly greater in the game intervention than in the normal intervention (P < 0.05).

Conclusions

A short-term intervention using an activity monitor with computerized game functions increases physical activity and reduces body fat more effectively than an intervention using a standard activity monitor.     

L-citrulline supplementation reverses the impaired airway relaxation in neonatal rats exposed to hyperoxia

Background

Hyperoxia is shown to impair airway relaxation via limiting L-arginine bioavailability to nitric oxide synthase (NOS) and reducing NO production as a consequence. L-arginine can also be synthesized by L-citrulline recycling. The role of L-citrulline supplementation was investigated in the reversing of hyperoxia-induced impaired relaxation of rat tracheal smooth muscle (TSM).

Methods

Electrical field stimulation (EFS, 2–20 V)-induced relaxation was measured under in vitro conditions in preconstricted tracheal preparations obtained from 12 day old rat pups exposed to room air or hyperoxia (>95% oxygen) for 7 days supplemented with L-citrulline or saline (in vitro or in vivo). The role of the L-citrulline/L-arginine cycle under basal conditions was studied by incubation of preparations in the presence of argininosuccinate synthase (ASS) inhibitor [α-methyl-D, L-aspartate, 1 mM] or argininosuccinate lyase inhibitor (ASL) succinate (1 mM) and/or NOS inhibitor [N^ω-nitro-L-arginine methyl ester; 100 μM] with respect to the presence or absence of L-citrulline (2 mM).

Results

Hyperoxia impaired the EFS-induced relaxation of TSM as compared to room air control (p < 0.001; 0.5 ± 0.1% at 2 V to 50.6 ± 5.7% at 20 V in hyperoxic group: 0.7 ± 0.2 at 2 V to 80.0 ± 5.6% at 20 V in room air group). Inhibition of ASS or ASL, and L-citrulline supplementation did not affect relaxation responses under basal conditions. However, inhibition of NOS significantly reduced relaxation responses (p < 0.001), which were restored to control level by L-citrulline. L-citrulline supplementation in vivo and in vitro also reversed the hyperoxia-impaired relaxation. The differences were significant (p <0.001; 0.8 ± 0.3% at 2 V to 47.1 ± 4.1% at 20 V without L-citrulline; 0.9 ± 0.3% at 2 V to 68.2 ± 4.8% at 20 V with L-citrulline). Inhibition of ASS or ASL prevented this effect of L-citrulline.

Conclusion

The results indicate the presence of an L-citrulline/L-arginine cycle in the airways of rat pups. L-citrulline recycling does not play a major role under basal conditions in airways, but it has an important role under conditions of substrate limitations to NOS as a source of L-arginine, and L-citrulline supplementation reverses the impaired relaxation of airways under hyperoxic conditions.     

Physical activity level and its clinical correlates in chronic obstructive pulmonary disease: a cross-sectional study

Background

Decreased physical activity is associated with higher mortality in subjects with COPD. The aim of this study was to assess clinical characteristics and physical activity levels (PALs) in subjects with COPD.

Methods

Seventy-three subjects with COPD (67 ± 7 yrs, 44 female) with one-second forced expiratory volume percentage (FEV₁%) predicted values of 43 ± 16 were included. The ratio of total energy expenditure (TEE) and resting metabolic rate (RMR) was used to define the physical activity level (PAL) (PAL = TEE/RMR). TEE was assessed with an activity monitor (ActiReg), and RMR was measured by indirect calorimetry. Walking speed (measured over 30-meters), maximal quadriceps muscle strength, fat-free mass and systemic inflammation were measured as clinical characteristics. Hierarchical linear regression was applied to investigate the explanatory values of the clinical correlates to PAL.

Results

The mean PAL was 1.47 ± 0.19, and 92% of subjects were classified as physically very inactive or sedentary. The walking speed was 1.02 ± 0.23 m/s, the quadriceps strength was 31.3 ± 11.2 kg, and the fat-free mass index (FFMI) was 15.7 ± 2.3 kg/m², identifying 42% of subjects as slow walkers, 21% as muscle-weak and 49% as FFM-depleted. The regression model explained 45.5% (p < 0.001) of the variance in PAL. The FEV₁% predicted explained the largest proportion (22.5%), with further improvements in the model from walking speed (10.1%), muscle strength (7.0%) and FFMI (3.0%). Neither age, gender nor systemic inflammation contributed to the model.

Conclusions

Apart from lung function, walking speed and muscle strength are important correlates of physical activity. Further explorations of the longitudinal effects of the factors characterizing the most inactive subjects are warranted.     

N-acetylcysteine improves established monocrotaline-induced pulmonary hypertension in rats

Background

The outcome of patients suffering from pulmonary arterial hypertension (PAH) are predominantly determined by the response of the right ventricle to the increase afterload secondary to high vascular pulmonary resistance. However, little is known about the effects of the current available or experimental PAH treatments on the heart. Recently, inflammation has been implicated in the pathophysiology of PAH. N-acetylcysteine (NAC), a well-known safe anti-oxidant drug, has immuno-modulatory and cardioprotective properties. We therefore hypothesized that NAC could reduce the severity of pulmonary hypertension (PH) in rats exposed to monocrotaline (MCT), lowering inflammation and preserving pulmonary vascular system and right heart function.

Methods

Saline-treated control, MCT-exposed, MCT-exposed and NAC treated rats (day 14–28) were evaluated at day 28 following MCT for hemodynamic parameters (right ventricular systolic pressure, mean pulmonary arterial pressure and cardiac output), right ventricular hypertrophy, pulmonary vascular morphometry, lung inflammatory cells immunohistochemistry (monocyte/macrophages and dendritic cells), IL-6 expression, cardiomyocyte hypertrophy and cardiac fibrosis.

Results

The treatment with NAC significantly decreased pulmonary vascular remodeling, lung inflammation, and improved total pulmonary resistance (from 0.71 ± 0.05 for MCT group to 0.50 ± 0.06 for MCT + NAC group, p < 0.05). Right ventricular function was also improved with NAC treatment associated with a significant decrease in cardiomyocyte hypertrophy (625 ± 69 vs. 439 ± 21 μm² for MCT and MCT + NAC group respectively, p < 0.001) and heart fibrosis (14.1 ± 0.8 vs. 8.8 ± 0.1% for MCT and MCT + NAC group respectively, p < 0.001).

Conclusions

Through its immuno-modulatory and cardioprotective properties, NAC has beneficial effect on pulmonary vascular and right heart function in experimental PH.     

Gender differences in right ventricular function in patients with non-ischaemic cardiomyopathy

Aim

To evaluate sex-related differences in right ventricular (RV) function, assessed with cardiac magnetic resonance imaging, in patients with stable non-ischaemic dilated cardiomyopathy.

Methods

Prospective multicentre study. We included 71 patients (38 men) and 14 healthy volunteers.

Results

Mean age was 60.9 ± 12.2 years. Men presented higher levels of haemoglobin and white blood cell counts than women, and performed better in cardiopulmonary stress testing. A total of 24 patients (12 women) presented severe left ventricular (LV) systolic dysfunction, 32 (13 female) moderate and 15 (8 women) mild LV systolic dysfunction. In the group with severe LV systolic dysfunction, average right ventricular ejection fraction (RVEF) was normal in women (52 ± 4 %), whereas it was reduced in men (39 ± 3 %) p = 0.035. Only one woman (8 %) had severe RV systolic dysfunction (RVEF < 35 %) compared with 6 men (50 %) p < 0.001. In patients with moderate and mild LV dysfunction , the mean RVEF was normal in both men and women. In the 14 healthy volunteers, the lowest value of RVEF was 48 % and mean RVEF was normal in women (56 ± 2 %) and in men (51 ±  1 %), p = 0.08.

Conclusions

In patients with dilated cardiomyopathy, RV systolic dysfunction is found mainly in male patients with severe LV systolic dysfunction.