Evaluating treatment response to mepolizumab in patients with severe CRSwNP.

BACKGROUND: The SYNAPSE study (NCT03085797) demonstrated that mepolizumab decreased nasal polyp (NP) size and nasal obstruction in patients with chronic rhinosinusitis with NP (CRSwNP). METHODS: SYNAPSE, a randomized, double-blind study, included patients with recurrent, refractory, severe CRSwNP, eligible for repeated surgery despite receiving standard of care (SoC). Patients received 4-weekly mepolizumab 100 mg or placebo subcutaneously plus SoC for 52 weeks. This post hoc analysis further characterized treatment responses and association with patient characteristics. The proportion of patients meeting any and each of five response criteria indicating improvement in disease-specific quality of life, NP size, nasal obstruction, loss of smell, and overall symptoms at Weeks 24 and 52, were assessed in subgroups: 1) no surgery; 2) neither surgery nor systemic corticosteroids (SCS). RESULTS: Of 407 patients in the intention-to-treat population, 381 and 343 patients had no sinus surgery by Weeks 24 and 52, respectively. More mepolizumab- versus placebo-treated patients without surgery by Weeks 24 and 52 met each response criteria. Of the mepolizumab-treated patients without surgery by Week 24, 109 (55%) responded across >=3 criteria, increasing to 126 (67%) by Week 52. Similar response trends were seen for patients with neither surgery nor SCS by Weeks 24 and 52. At either timepoint, there were no major differences in baseline characteristics between mepolizumab-treated full- (5/5 categories) and non-responders (0/5 categories). CONCLUSIONS: Most patients who completed SYNAPSE required neither surgery nor SCS use and in addition achieved a progressive and sustained clinical response to mepolizumab underscoring the therapeutic benefits of mepolizumab in severe CRSwNP.

Mepolizumab improves quality of life and reduces activity impairments in patients with CRSwNP.

Mepolizumab improves quality of life and reduces activity impairments in patients with CRSwNP.

Responsiveness to oral prednisolone in severe asthma is related to the degree of eosinophilic airway inflammation.

BACKGROUND: Patients with severe asthma appear relatively corticosteroid resistant. Corticosteroid responsiveness is closely related to the degree of eosinophilic airway inflammation. The extent to which eosinophilic airway inflammation in severe asthma responds to treatment with systemic corticosteroids is not clear. OBJECTIVE: To relate the physiological and inflammatory response to systemic corticosteroids in asthma to disease severity and the baseline extent of eosinophilic inflammation. METHODS: Patients with mild/moderate and severe asthma were investigated before and after 2 weeks of oral prednisolone (Clintrials.gov NCT00331058 and NCT00327197). We pooled the results from two studies with common protocols. The US study contained two independent centres and the UK one independent centre. The effect of oral corticosteroids on FEV1 , Pc20, airway inflammation and serum cytokines was investigated. Baseline measurements were compared with healthy subjects. RESULTS: Thirty-two mild/moderate asthmatics, 50 severe asthmatics and 35 healthy subjects took part. At baseline, both groups of asthmatics had a lower FEV1 and Pc20 and increased eosinophilic inflammation compared to healthy subjects. The severe group had a lower FEV1 and more eosinophilic inflammation compared to mild/moderate asthmatics. Oral prednisolone caused a similar degree of suppression of eosinophilic inflammation in all compartments in both groups of asthmatics. There were small improvements in FEV1 and Pc20 for both mild/ moderate and severe asthmatics with a correlation between the baseline eosinophilic inflammation and the change in FEV1 . There was a ~50% reduction in the serum concentration of CXCL10 (IP-10), CCL22 (MDC), CCL17 (TARC), CCL-2 (MCP-1) and CCL-13 (MCP-4) in both asthma groups after oral corticosteroids. CONCLUSIONS AND CLINICAL RELEVANCE: Disease severity does not influence the response to systemic corticosteroids. The study does not therefore support the concept that severe asthma is associated with corticosteroid resistance. Only baseline eosinophilic inflammation was associated with the physiological response to corticosteroids, confirming the importance of measuring eosinophilic inflammation to guide corticosteroid use.

Bee's morphometrics and behavior in response to seasonal effects from ecoregions.

In the present study, we used morphological and behavioral analyses to assess the effects of seasonality and morphoclimatic patterns on the morphology, behavior, and distribution of 71 colonies of Africanized honey bees in 3 distinct ecoregions (Zona da Mata, Agreste, and Sertão) within the State of Sergipe, north-eastern Brazil. We found a high rate of gene flow among the studied colonies. However, there were pronounced morphological differences among localities and ecoregions, and body shape (r = 0.06239; P = 0.05) and size (P < 0.001) varied with altitude. Regional groups were separated by phenotypic plasticity, rather than genetic divergence. We also found a significant difference in the hygienic behavior of these populations between the dry and rainy seasons (P = 0.022; α = 0.05) and between ecoregions (P = 0.001; α = 0.05). The main modulator of hygienic behavior was the influence of temperature (ρ = 0.065; P = 0.471; α = 0.05) and altitude (ρ = -0.294; P = 0.001; α = 0.05) on rainfall (ρ = 0.274; P = 0.002; α = 0.05). This supports the hypothesis that environmental factors influence the expression of hygienic behavior trait. The influence of environmental factors on the morphology, behavior, and distribution of Africanized honey bees, together with the identified polyphenisms, indicate high genetic variability within these populations that can be exploited in future bee handling and breeding programs.

External validation of blood eosinophils, FE(NO) and serum periostin as surrogates for sputum eosinophils in asthma.

BACKGROUND: Monitoring sputum eosinophils in asthma predicts exacerbations and improves management of asthma. Thus far, blood eosinophils and FE(NO) show contradictory results in predicting eosinophilic airway inflammation. More recently, serum periostin was proposed as a novel biomarker for eosinophilic inflammation. OBJECTIVES: Quantifying the mutual relationships of blood eosinophils, FE(NO), and serum periostin with sputum eosinophils by external validation in two independent cohorts across various severities of asthma. METHODS: The first cohort consisted of 110 patients with mild to moderate asthma (external validation cohort). The replication cohort consisted of 37 patients with moderate to severe asthma. Both cohorts were evaluated cross-sectionally. Sputum was induced for the assessment of eosinophils. In parallel, blood eosinophil counts, serum periostin concentrations and FENO were assessed. The diagnostic accuracy of these markers to identify eosinophilic asthma (sputum eosinophils ≥3%) was calculated using receiver operating characteristics area under the curve (ROC AUC). RESULTS: In the external validation cohort, ROC AUC for blood eosinophils was 89% (p<0.001) and for FE(NO) level 78% (p<0.001) to detect sputum eosinophilia ≥3%. Serum periostin was not able to distinguish eosinophilic from non-eosinophilic airway inflammation (ROC AUC=55%, p=0.44). When combining these three variables, no improvement was seen. The diagnostic value of blood eosinophils was confirmed in the replication cohort (ROC AUC 85%, p<0.001). CONCLUSIONS: In patients with mild to moderate asthma, as well as patients with more severe asthma, blood eosinophils had the highest accuracy in the identification of sputum eosinophilia in asthma. The use of blood eosinophils can facilitate individualised treatment and management of asthma. TRIAL REGISTRATION: NTR1846 and NTR2364.

Safety and efficacy of an oral CCR3 antagonist in patients with asthma and eosinophilic bronchitis: a randomized, placebo-controlled clinical trial.

BACKGROUND: Several chemokines, notably eotaxin, mediate the recruitment of eosinophils into tissues via the CCR3 receptor. OBJECTIVE: In this study, we investigated the role of CCR3 agonists in asthma by observing the effect of a small molecule antagonist of the CCR3 receptor (GW766994) on sputum eosinophil counts in patients with eosinophilic asthma. METHODS: Clinical and physiological outcomes, the chemotactic activity of sputum supernatant for eosinophils and the presence of eosinophil progenitors in sputum and blood samples were also studied. RESULTS: In a double-blind parallel group study, 60 patients with asthma were randomized to 300 mg of GW766994 twice daily or matching placebo for 10 days followed by prednisone 30 mg for 5 days. Of these patients, 53 had a sputum eosinophil count > 4.9% at baseline. Despite plasma concentrations of drug consistent with > 90% receptor occupancy during the dosing period, the CCR3 antagonist did not significantly reduce eosinophils or eosinophil progenitor cells (CD34(+) 45(+) IL-5Rα(+)) in sputum or in blood. The ex vivo chemotactic effect of sputum supernatants on eosinophils was attenuated by GW766944 compared to placebo. There was no improvement in FEV1 ; however, there was a modest but statistically significant improvement in PC20 methacholine (0.66 doubling dose) and ACQ scores, (0.43). Whilst the improvement in PC20 is statistically significant, it is not of clinical significance. CONCLUSIONS AND CLINICAL RELEVANCE: In conclusion, this study calls into question the role of CCR3 in airway eosinophilia in asthma and suggests that other cellular mechanisms mediated by the CCR3 receptor may contribute to airway hyperresponsiveness.

Intraoperative transesophageal echocardiogram using an intracardiac ultrasound catheter in a congenital heart surgery: a case report.

Transesophageal echocardiography (TEE) during cardiac surgery is a routine procedure. The use of pediatric TEE probes is limited in small infants weighing less than 5 kg. Recent reports have shown the safety of monoplane intravascular ultrasound catheters in transesophageal echocardiograms. This report describes the case of a newborn with total anomalous pulmonary venous return who underwent cardiac surgery. A pre- and postbypass TEE examination was performed, with successful visualization of the cardiac anatomy and function and no complications.

Blood delta-ALAD, lead and cadmium concentrations in spur-thighed tortoises (Testudo graeca) from Southeastern Spain and Northern Africa.

Mediterranean spur-thighed tortoise (Testudo graeca) is actually included in the IUCN as vulnerable species. Its main European population is located in southeastern Spain. Although a great deal of information has been acquired on the internal medicine and survey and even parasitological fauna on these animals, there are no references about contaminants levels in this species. The objectives of this study were to compare the levels of two metals (cadmium and lead) in the blood of spur-thighed tortoises from two different populations, one from Southeastern of Spain (n = 22) and the other from North of Africa (n = 39), kept in captivity at the Santa Faz Recuperation Centre (Alicante, Spain) and to investigate the relationship between their blood levels of lead and their blood delta-aminolevulinic acid dehydratase (delta-ALAD) activity. Blood lead and cadmium concentrations were higher in tortoises from African than in those from Spain. Moreover, a negative and significant correlation (P < 0.05) was found between delta-ALAD activity and blood lead levels, indicating the suitability of this enzyme as biomarker for lead in this species.

Sputum proteomic signature of gastro-oesophageal reflux in patients with severe asthma.

Gastro-oesophageal reflux disease (GORD) has long been associated with poor asthma control without an established cause-effect relationship. 610 asthmatics (421 severe/88 mild-moderate) and 101 healthy controls were assessed clinically and a subset of 154 severe asthmatics underwent proteomic analysis of induced sputum using untargeted mass spectrometry, LC-IMS-MSE. Univariate and multiple logistic regression analyses (MLR) were conducted to identify proteins associated with GORD in this cohort. When compared to mild/moderate asthmatics and healthy individuals, respectively, GORD was three- and ten-fold more prevalent in severe asthmatics and was associated with increased asthma symptoms and oral corticosteroid use, poorer quality of life, depression/anxiety, obesity and symptoms of sino-nasal disease. Comparison of sputum proteomes in severe asthmatics with and without active GORD showed five differentially abundant proteins with described roles in anti-microbial defences, systemic inflammation and epithelial integrity. Three of these were associated with active GORD by multiple linear regression analysis: Ig lambda variable 1-47 (p = 0·017) and plasma protease C1 inhibitor (p = 0·043), both in lower concentrations, and lipocalin-1 (p = 0·034) in higher concentrations in active GORD. This study provides evidence which suggests that reflux can cause subtle perturbation of proteins detectable in the airways lining fluid and that severe asthmatics with GORD may represent a distinct phenotype of asthma.

Serum YB-1 (Y-box binding protein 1) as a biomarker of bone disease progression in patients with breast cancer and bone metastases.

YB-1 (Y-box binding protein 1) is a multifunctional cold-shock protein that has been implicated in all hallmarks of cancer. Elevated YB-1 protein level was associated with poor prognosis in several types of cancers, including breast cancer (BC), where it is a marker of decreased overall survival (OS) and distant metastasis-free survival across all subtypes. YB-1 is also secreted by different cell types and may act as an extracellular mitogen; however the pathological implications of the secreted form of YB-1 (sYB-1) are unknown. Our purpose was to retrospectively evaluate the association between YB-1 measured by ELISA in serum and disease characteristics and outcomes in patients with BC and bone metastases (BM). In our cohort, sYB-1 was detected in the serum of 22 (50%) patients, and was associated with the presence of extra-bone metastases (p=0.044). Positive sYB-1 was also associated with faster bone disease progression (HR 3.1, 95% CI 1.09-8.95, P=0.033), but no significant differences were observed concerning OS, and time to development of skeletal-related events. Moreover, patients with positive sYB-1 also had higher levels of IL-6, a known osteoclastogenic inducer. Therefore, detection of sYB-1 in patients with BC and BM may indicate a higher tumor burden, in bone and extra-bone locations, and is a biomarker of faster bone disease progression.

[Surgical treatment of ventricular septal defect in the first year of life]. / Tratamento cirúrgico da comunicação interventricular no primeiro ano de vida.

Forty six infants with a large ventricular septal defect (VSD) underwent surgical treatment during the first 12 months of life. Forty three patients ranging in age from 3 to 12 months (mean age 10.4 months) and weighting from 3.0 to 8.2 kg (mean weight 6.8 kg) had primary surgical closure of their VSD. All infants were below the third percentile for weight preoperatively. In 40 patients (93%) the defect was closed through the right atrium. Three patients (7.0%) died in the early postoperative period. Surgically induced heart block occurred in one patient (2.3%). Late results were assessed in 29 surgical survivors (mean follow-up 26 months). There was no late mortality. Relief of congestive heart failure was prompt in all patients following closure of VSD. Right bundle branch block with left anterior hemiblock developed in 5 patients (17.2%), and right bundle branch block alone in 10 patients (34.5%). Three patients (mean age 4.3 months, mean weight 2.7 kg) underwent initial palliative pulmonary artery banding (PAB). There were no operative or late mortality. Closure of VSD and pulmonary artery debanding was performed in two of these patients, with no mortality. Prior to intracardiac correction the pulmonary artery pressure distal to the band was normal; no band related complications were found. Early primary closure is the treatment of choice for symptomatic infants with large VSDs. In particular circumstances, however, PAB may provide effective palliation.

[Aorto-left ventricular tunnel arising from the left sinus of Valsalva]. / Túnel aorta-ventrículo esquerdo com origem no seio de Valsalva esquerdo.

Aortic-left ventricular tunnel (ALVT) is a rare congenital anomaly in which an abnormal communication connects the ascending aorta with the left ventricle, bypassing the aortic valve. Usually the ALVT takes its origin from the right aortic sinus. We report a patient with an ALVT arising from the left sinus of Valsalva who underwent surgery at five months of age. The diagnosis was first established by two-dimensional echocardiography.

[Vascular rings: surgical treatment]. / Anéis vasculares: tratamento cirúrgico.

From 1982 to 1992, nine patients underwent correction of vascular rings. The diagnosis was strongly suggested by symptoms of tracheoesophageal obstruction and was confirmed by barium esophagogram and angiography. Endoscopic studies were considered unnecessary and potentially harmful. Seven patients had double aortic arch, one patient right aortic arch with aberrant left subclavian artery and left ligamentum arteriosum and one patient anomalous origin of the left pulmonary artery. The anomaly was approached through a left thoracotomy in every patient. There were no operative or late deaths. When patients are symptomatic, vascular rings should be promptly repaired. The surgical risk is minimal, and the long term results are excellent.

[Echocardiographic assessment of interventricular septal defect corrected during the first year of life]. / Avaliação ecocardiográfica da comunicação interventricular corrigida no primeiro ano de vida.

OBJECTIVE: To evaluate the medium term results of surgical closure of ventricular septal defect (VSD) performed during the first year of life, using echocardiography (echo). MATERIAL AND METHODS: We studied prospectively 29 patients aged from 17 to 68 months (mean = 37) who underwent surgical closure of perimembranous VSD during the first year of life. The postoperative follow-up time ranged from 6 to 60 months (mean = 26). Fifteen age-matched normal children were used as a control group in evaluating the left ventricular (LV) systolic function. The echo study included: 1) the assessment of LV systolic function using the shortening fraction, ejection fraction, pre-ejection to ejection time ratio (PET/ET), aortic flow acceleration time, acceleration to ejection time ratio, mean aortic flow acceleration; 2) detection and quantification of residual VSD as well as tricuspid and or aortic regurgitation; 3) determination of right ventricular systolic pressure (RVSP). The RVSP was evaluated from the maximum flow velocity from a residual VSD or tricuspid regurgitation, using the simplified Bernoulli equation. RESULTS: The LV systolic function parameters from patients versus (vs) normals showed a significantly different shortening fraction (34 +/- 5 vs 39 +/- 4; p = 0.005) and PET/ET ratio (0.34 +/- 0.04 vs 0.31 +/- 0.03; p = 0.02). None of the other studied parameters was significantly different from normal. Five (17%) patients had a small residual VSD. Two (7%) patients had mild aortic regurgitation. Tricuspid regurgitation was detected in 23 (79%) patients being trivial in 20 and mild to moderate in 3. The RVSP was quantified in 22 (76%) patients, ranging from 30 to 45 mmHg (mean +/- SD = 36 +/- 4). None of the remaining 7 patients showed changes in the end-systolic interventricular septal configuration. CONCLUSIONS: Our study shows that surgical closure of perimembranous VSD performed during the first year of life was possible without significant mobility. Furthermore, the echo allowed a complete and noninvasive cardiac evaluation of the anatomic, functional and hemodynamic status of this group of patients, thus limiting the need for postoperative control cardiac catheterization.

Audit of headache following resection of acoustic neuroma using three different techniques of suboccipital approach.

A retrospective case notes review using pain visual analogue scale (VAS) and assessment of analgesia required by patients in the post-operative period at 1, 3, 6, 12 and over 12 months following acoustic neuroma resection was performed. Glasgow Benefit Inventory (GBI) score was used to assess the change of quality of life and its relationship to pain following surgery. Questionnaires of 71 patients were included in the study, 23 of whom underwent wide craniotomy including dissection of upper cervical musculature (CE), 25 wide craniotomy with replacement of bone flap (CO) and 23 minimally invasive, approximately 2 x 2 cm, minicraniectomy (MCE). The minicraniectomy resulted in significantly diminished pain from third month post surgery as compared with wide craniectomy (p < 0.05) and patients required less analgesia. Similarly, CO patients have experienced significantly less pain than CE patients (p < 0.05), but only after 12 months following surgery. Although consistently less in absolute visual analogue scores, there was no statistically significant difference between the amount of pain recorded by CO and MCE patients. There was no correlation between gender or age and the VAS pain score. The mean Glasgow Benefit Inventory score for all patients was -6.6, and there was no significant difference between operation types, genders or age. Although bone flap replacement appears to diminish the amount of post-operative pain, minimal invasive technique resulted in least pain following acoustic neuroma resection in our patients.

[Upper cleft of the sternum]. / Fenda superior do esterno.

Superior sternal cleft is a rare congenital malformation that should be repaired during the first weeks of life, while the thorax is still complaint. We report the case of a two-week-old neonate with superior sternal cleft and describe the technique used to close the defect.

Production of hybrid lipid-based particles loaded with inorganic nanoparticles and active compounds for prolonged topical release.

The production of particulate hybrid carriers containing a glyceryl monostearate (Lumulse GMS-K), a waxy triglyceride (Cutina HR), silanized TiO(2) and caffeine were investigated with the aim of producing sunscreens with UV-radiation protection properties. Particles were obtained using the supercritical PGSS (Particles from Gas Saturated Solutions) technique. This method takes advantages of the lower melting temperatures of the lipids obtained from the dissolution of CO(2) in the bulk mixture. Experiments were performed at 13 MPa and 345 K, according to previous melting point measurements. Blends containing Lumulse GMS-K and Cutina HR lipids (50 wt%) were loaded with silanized TiO(2) and caffeine in percentile proportions of 6 and 4 wt%, respectively. The particles produced were characterized using several analytical techniques as follows: system crystallinity was checked by X-ray diffraction and differential scanning calorimetry, thermal stability by thermogravimetric analysis, and morphology by scanning and transmission electron microscopy. Further, the UV-shielding ability of TiO(2) after its dispersion in the lipidic matrix was assessed by solid UV-vis spectroscopy. Preliminary results indicated that caffeine-loaded solid lipid particles presented a two-step dissolution profile, with an initial burst of 60 wt% of the loaded active agent. Lipid blends loaded with TiO(2) and caffeine encompassed the UV-filter behavior of TiO(2) and the photoaging prevention properties of caffeine.

Subepithelial immunopathology of the large airways in smokers with and without chronic obstructive pulmonary disease.

Previous work has shown an increase in CD8+ T-cells, neutrophils and eosinophils in small airway subepithelium in smokers. The authors have now investigated whether similar changes occur in the large airways. Immunohistochemistry on frozen sections of bronchial biopsies were obtained at bronchoscopy in 11 nonsmokers, eight asymptomatic smokers and 11 smokers with chronic bronchitis and chronic obstructive pulmonary disease (COPD). There was an increase in the number of CD8+ cells infiltrating the bronchial subepithelium in the COPD group compared to the asymptomatic smokers (305 (109-400) versus 92 (41-550) cells x mm(-2), p=0.030). There was a negative correlation between the number of CD8+ cells and the forced expiratory volume in one second (FEV1) %predicted (p=0.005, r=-0.62), and a positive correlation between the number of CD8+ cells and the number of pack years smoked (p=0.017, r=0.42). There was a negative correlation between the activated/total eosinophils ratio and the FEV1 % pred (p=0.017, r=-0.51). There was a negative correlation between pack years smoked and the number of neutrophils (p=0.022, r=-0.36). Smokers who develop chronic obstructive pulmonary disease have increased numbers of CD8+ T-cells in large airways when compared to asymptomatic smokers. Airway obstruction was associated with an increase in the proportion of eosinophils that were activated.