Nasal indices of eosinophilic and exudative inflammation in bakery-workers

AIMS: Rhinitis symptoms frequently occur in bakery-workers. Yet, little is known about the pathophysiology of this condition. The objective of the present study was to examine nasal indices of inflammation in relation to occupational dust exposure, occupational rhinitis according to defined criteria, rhinitis symptoms associated to the workplace, and occupational sensitization in bakery-workers. METHODS: Bakery-workers (n = 197) were subjected to interviews, questionnaires, workplace dust measurements, allergy tests, and nasal lavages with and without histamine. alpha(2)-Macroglobulin and eosinophil cationic protein (ECP) were measured in saline lavages as indices of plasma exudation and eosinophilic activity, respectively. Histamine lavages were employed to explore the nasal exudative responsiveness. RESULTS: alpha(2)-Macroglobulin and ECP increased significantly by increased workplace dust exposure (P< or =0.035). Furthermore, the exudative responsiveness to histamine increased significantly by such exposure (P< or =0.016). Similar patterns were seen in workers with occupational rhinitis and in subjects with rhinitis symptoms associated to the workplace, but not in workers with occupational sensitization. CONCLUSIONS: We conclude that occupational dust exposure in bakery-workers is associated with nasal eosinophilic exudative inflammation. In contrast, occupational sensitization is not a discriminating factor with regard to indices of eosinophilic, exudative inflammation in the present material.     

修正性鼻内镜手术联合克拉霉素治疗复发性慢性鼻-鼻窦炎疗效研究

目的探讨修正性鼻内镜手术联合克拉霉素治疗复发性慢性鼻-鼻窦炎(RCRS)的疗效。方法根据治疗方法的不同,将2009年12月至2015年6月诊治的62例RCRS患者分为单独修正性鼻内镜手术组(单独组)和修正性鼻内镜手术联合克拉霉素组(联合组),每组各31例。比较两组患者临床疗效及其他指标。结果治疗后两组患者鼻塞、流涕、头痛和嗅觉减退评分均显著改善(P0.05),联合组鼻塞、流涕、头痛和嗅觉减退评分均明显低于单独组(P0.05)。联合组治疗有效率为90.32%,明显高于单独组的64.52%(P0.05)。疗程结束后,两组患者黏膜纤毛传输速率水平显著升高(P0.05),联合组黏膜纤毛传输速率改善程度优于单独组(P0.05)。联合组术腔清洁时间和上皮化时间明显短于单独组(P0.05)。结论修正性鼻内镜手术后予以克拉霉素可显著提高RCRS临床疗效。     

Bronchial responsiveness in bakery workers: relation to airway symptoms, IgE sensitization, nasal indices of inflammation, flour dust exposure and smoking

BACKGROUND: Bronchial hyperresponsiveness (BHR) is common in bakery workers. The relation between bronchial responsiveness measured with a tidal breathing method and smoking, airway symptoms, IgE-sensitization, nasal indices of inflammation and flour dust exposure have been studied with bronchial responsiveness expressed as a continuous outcome. MATERIAL AND METHODS: Bakery workers (n = 197) were subjected to interviews, questionnaires, allergy tests, workplace dust measurements and bronchial metacholine provocation. Eosinophil cationic protein (ECP) and alpha(2)-macroglobulin were measured in nasal lavage. Bronchial responsiveness was expressed as slope(conc), a measurement based on regressing the per cent reduction in FEV(1) at each provocation step. RESULTS: BHR expressed as slope(conc) was associated with smoking (P = 0.009), asthma symptoms at work (P = 0.001), and occupational IgE sensitization (P = 0.048). After adjusting for baseline lung function the association between BHR and IgE sensitization was no longer present. We demonstrated an association between nasal ECP and BHR (slope(conc) < 3: P = 0.012), but not to alpha(2)-macroglobulin in nasal lavage. No association was seen between BHR and current exposure level of flour dust, number of working years in a bakery or a history of dough-making. CONCLUSION: BHR is related to baseline lung function, work-related asthma symptoms, smoking and nasal eosinophil activity, but not to occupational IgE sensitization and current flour dust exposure when measured with metacholine provocation. The slope(conc) expression seems to be a useful continuous outcome in bronchial responsiveness testing.     

Effects of variation in the human α2A‐ and α2C‐adrenoceptor genes on cognitive tasks and pain perception

Background: The mechanisms underlying interindividual variability in pain perception and cognitive responses are undefined but highly heritable. α_2C‐ and α_2A‐adrenergic receptors regulate noradrenergic activity and are important mediators of pain perception and analgesia. We hypothesized that common genetic variants in these genes, particularly the ADRA2C 322–325 deletion variant, affect pain perception or cognitive responses. Methods: We studied 73 healthy subjects (37 Caucasians and 36 African–Americans) aged 25.4 ± 4.6 years. Pain response to a cold pressor test was measured using a 10 cm visual analog scale and again on the next day, after three infusions of the selective α₂‐agonist dexmedetomidine. Standardized cognitive tests were administered at baseline and after each infusion. The contribution of ADRA2C deletion genotype, dexmedetomidine concentration, and other covariates to pain perception and cognitive responses was determined using multiple linear regression models. Secondary analysis examined the effects of ADRA2A and other ADRA2C variants on pain perception. Results: ADRA2C Del homozygotes had higher pain scores in response to cold at baseline (6.3 ± 1.8 cm) and after dexmedetomidine (5.6 ± 2.2 cm) than insertion allele carriers (4.6 ± 2.1 cm [baseline] and 3.8 ± 1.9 cm [after dexmedetomidine]; adjusted P‐values = 0.019 and 0.004, respectively). Cognitive responses were unrelated to ADRA2C Ins/Del genotype. None of the other ADRA2A and ADRA2C variants was significantly related to cold pain sensitivity before dexmedetomidine; after dexmedetomidine, ADRA2A rs1800038 was marginally associated (P = 0.03). Conclusion: The common ADRA2C del322–325 variant affected pain perception before and after dexmedetomidine but did not affect other cognitive responses, suggesting that it contributes to interindividual variability in pain perception.     

Comparative study of alpha‐ and beta‐pinene effect on PTZ‐induced convulsions in mice

Convulsions occur in response to a loss of balance between excitatory and inhibitory neurotransmitters, and the treatment for this condition consists in restore such lost balance. Many anticonvulsant drugs present side effects which may limit their use. This fact has stimulated the search for new sources of treatment from aromatic plants. Many monoterpenes commonly present in essential oils are known because of their anticonvulsant properties. The anticonvulsant effect of α‐ and β‐pinene, two structural isomers, is still little studied. Thus, the present work evaluated the anticonvulsant effect of α‐ and β‐pinene in pentylenetetrazole‐induced convulsions model. Initially, the oral LD₅₀ for α‐ and β‐pinene was estimated. Following the oral administration, a mild sedation was observed and no deaths were recorded; the LD₅₀ estimated for both monoterpenes was greater than 2 000 mg/kg, p.o. Further, animals were orally treated with α‐pinene (100, 200 and 400 mg/kg), β‐pinene (100, 200 and 400 mg/kg) and the equimolar mixture of α‐ and β‐pinene (400 mg/kg) and subjected to the pentylenetetrazole‐induced convulsions model. In this model, only the dose of 400 mg/kg of the compounds was able to significantly decrease the seizure intensity. The latency of first convulsion was significantly increased by the mixture of α‐ and β‐pinene (400 mg/kg). In addition, β‐pinene and the mixture of the two monoterpenes, both at a dose of 400 mg/kg, significantly increased the time of death of animals. The treatment with β‐pinene and the equimolar mixture of the two monoterpenes significantly reduced hippocampal nitrite level and striatal content of dopamine (DA) and norepinephrine (NE). Taken together, the results suggest that α‐pinene appears to be devoid of anticonvulsant action. This fact, however, seems to be dependent on the chemical structure of the compound, since pretreatment with the β‐pinene increased the time of death pf PTZ‐treated mice, which seems to depend on the ability of the compound to reduce nitrite concentration and NE and DA content, during the pentylenetetrazole‐induced seizure.     

Associations of IgG N‐linked oligosaccharide chains and proteases in sera of prostate cancer patients with and without α2‐macroglobulin deficiency

We previously reported on a number of cases of metastatic prostate cancer (PCa) in which serum α2‐macroglobulin (α2M) levels were markedly decreased to less than 20 mg/dl (α2M deficiency). All PCa patients with α2M deficiency had multiple bone metastases. Proteases in ten PCa patients with and without α2M deficiency were studied and compared against ten healthy controls in order to elucidate the relationships between changes in sugar chain structure and neoplasia. We assessed the relationship between ratios of Fr4 to Fr1 and Fr2 (Fr4/Fr1+Fr2 ratios) of oligosaccharide chains, and ratios of free prostate‐specific antigen (PSA) to total PSA (F/T ratios), and serum levels of matrix‐metalloproteinase‐2 (MMP‐2) in PCa progression. Measurement of serum α2M concentration was performed by laser nephelometry. Serum PSA and MMP‐2 levels were determined by enzyme immunoassay and free PSA by radioimmunoassay. N‐linked oligosaccharides of human serum immunoglobulin G were analyzed using fluorophore‐associated carbohydrate electrophoresis. In those PCa patients with α2M deficiency: (a) serum α2M and F/T ratios were lower (P<0.05) and (b) Fr4/Fr1+Fr2 ratios and serum MMP‐2 levels were higher when compared with those PCa patients without α2M deficiency. There was a significant correlation between Fr4/Fr1+Fr2 ratios and F/T ratios or serum MMP‐2 levels in PCa with α2M deficiency (P<0.05). Therefore, these markers may serve as an auxiliary serum tumor marker for monitoring of the bone metastases or progression of disease in PCa. J. Clin. Lab. Anal. 23:125–131, 2009. © 2009 Wiley‐Liss, Inc.     

The calcification potential of human MSCs can be enhanced by interleukin‐1β in osteogenic medium

Inflammation is one of the key regulators of the repair process in bone tissues. Current data about the effect of interleukin‐1β (IL‐1β) on MSCs and osteoblasts are conflicting. We investigated the long‐term effect of IL‐1β on direct osteogenic differentiation of hMSCs in vitro. IL‐1β‐stimulated cells showed enhanced proliferation and entered maturation prior to non‐stimulated ones, as monitored by ALP activity. The process of calcification was accelerated during long‐term stimulation of hMSCs with IL‐1β. Since donor variability is a well‐known issue, we suggest a new method to illustrate global changes of a random chosen donor population through collative analysis. We further demonstrate an absorbance assay to evaluate the degree of calcification during in vitro culture of monolayer expanded hMSCs. Our findings support the importance of IL‐1β in osteogenic differentiation of hMSCs in an in vitro monolayer culture model. A new online absorbance assay is a useful method to evaluate the osteogenic differentiation of hMSCs at early stages. These findings will be helpful in optimizing predifferentiation of hMSCs in vitro for bone tissue engineering. Copyright © 2014 John Wiley & Sons, Ltd.     

Challenge-induced plasma exudation and mucinous secretion in human airways

Secretion of mucins and exudation of plasma are distinct processes of importance to innate immunity and inflammatory disease. Yet, little is known about their relation in human airways. The objective of the present study was to use the human nasal airway to determine mucinous secretion and plasma exudation in response to common challenge agents and mediators. Ten healthy volunteers were subjected to nasal challenge-lavage procedures. Thus, the nasal mucosa was exposed to increasing doses of histamine (40 and 400 microg ml(-1)), methacholine (12.5 and 25 mg) and capsaicin (30 and 300 ng ml(-1)). Fucose was selected as a global marker of mucinous secretion and alpha(2)-macroglobulin as an index of exudation of bulk plasma. All challenge agents increased the mucosal output of fucose to about the same level (P<0.01-0.05). Once significant secretion had been induced the subsequently increased dose of the challenge agent, in the case of histamine and methacholine, failed to further increase the response. Only histamine increased the mucosal output of alpha(2)-macroglobulin (P<0.01). We conclude that prompt but potentially rapidly depleted mucinous secretion is common to different kinds of airway challenges, whereas inflammatory histamine-type mediators are required to produce plasma exudation. Along with the acknowledged secretion of mucins, a practically non-depletable, pluripotent mucosal output of plasma emerges as an important component of the innate immunity of human airways.     

Anti‐inflammatory effect of 4‐methylcyclopentadecanone in rats submitted to ischemic stroke

This study aimed to investigate the anti‐inflammatory effect of 4‐methylcyclopentadecanone (4‐MCPC) in rats suffering from a cerebral ischemia/reperfusion (I/R) injury. In this study, the focal cerebral ischemia in rats was induced by middle cerebral artery occlusion (MCAO) for 2 h, and the rats were treated with 4‐MCPC (8 mg/kg) just 0.5 h before reperfusion. The ischemic infarct volume was recorded 24 h after the MCAO. In addition, myeloperoxidase (MPO) activity and TNF‐α and IL‐1β levels in the ischemic cerebral cortex were determined by ELISA, while nuclear translocation of NF‐κB p65 subunit and expression of p‐IκBα were investigated by Western blotting. Our results showed that 4‐MCPC treatment decreased infarct volume significantly, compared with I/R group (16.8%±7.5% vs. 39.7%±10.9%); it reduced MPO activity (0.43 ± 0.10 vs. 1.00 ± 0.51 U/g) and expression levels of TNF‐α (18.90 ± 3.65 vs. 35.87 ± 4.87 ng/g) and IL‐1β (1.68 ± 0.23 vs. 2.67 ± 0.38 ng/g) in ischemic brain tissues of rats. Further study revealed that 4‐MCPC treatment markedly reduced nuclear translocation of NF‐κB p65 subunit and expression of p‐IκBα in ischemic cerebral cortex. Taken together, our results suggest that 4‐MCPC protects against cerebral I/R injury and displays anti‐inflammatory actions through inhibition of the NF‐κB signal pathway.     

Effects of extracellular fluid volume changes on renal response to low-dose dopamine infusion in normal women

Summary. Dopamine (DA) i.v. infused in a low dose (0·1 (μg/kg/min) in healthy women during sustained hypotonic polyuria, produced different renal functional effects as variations in extracellular fluid volume occurred. (1) In hydro-saline retention (n= 23), induced by desoxycorticosterone acetate treatment, DA produced typical vasodilator and hydro-natriuretic effects (Goldberg, 1972). (2) In hydro-saline depletion (n= 19), induced by diuretic treatment and low dietary sodium intake, DA lost its vasodilator and natriuretic efficacy, manifesting, on the other hand, renal sodium conserving effects mainly dependent on the increase in distal sodium reabsorption and a trend towards afferent arteriolar vasoconstriction. (3) Treatment with prazosin (n= 9) or propranolol (n= 9) in hydro-saline depletion, was efficacious in partly restoring the typical vasodilator and natriuretic effects of DA. Thus, in hydro-saline depletion, DA produced sympathomimetic effects which were sufficiently intense to outweigh those due to activation of specific DA renal receptors.     

Neuropharmacological effects of lipoic acid and ubiquinone on the mRNA level of interleukin‐1β and acetylcholinesterase activity in rat hippocampus after seizures

The purpose of this study was to investigate the neuroprotective effects of lipoic acid and ubiquinone on interleukin‐1β (IL‐1β) mRNA levels and acetylcholinesterase (AChE) activities in rat hippocampus after pilocarpine‐induced seizures. Wistar rats were intraperitoneally administered with either 0.9% saline (icontrol group), LA (10 or 20 mg/kg, LA10 or LA20 groups), UQ (20 or 40 mg/kg, UQ20 and UQ40 groups), pilocarpine (400 mg/kg, P400 group), or co‐administration of pilocarpine with LA or UQ groups 30 min prior to LA or UQ administration. After the treatments, all groups were observed for 1 h. IL‐1β mRNA and AChE activity in rat hippocampus at 1 h after SE onset was determined. Results showed that rats pretreated with LA or UQ developed less seizures and SE more slowly and has less number than animals treated with pilocarpine alone. Reduced IL‐1β mRNA and marked AChE activities in the hippocampus were significantly higher in rats pretreated with LA or UQ in comparison with the values of the control and seized groups. Our findings strongly support the hypothesis that an increase on IL‐1β mRNA levels in hippocampus occurs during seizures induced by pilocarpine, which indicates that inflammatory process plays a crucial role in seizures pathogenic consequences. Our result also suggests that LA or UQ can exert significant neuroprotective effects, at least in part, because of the increase in the AChE activities in rat hippocampus that will be useful in the treatment of neurodegenerative diseases.     

嗜酸性阳离子蛋白在慢性阻塞性肺疾病与支气管哮喘诊断中的临床价值

目的检测慢性阻塞性肺疾病（chronic Obstructive pulmonary diseases, COPD） 患者血清中的嗜酸性阳离子蛋白（eosinophil cationic protein, ECP）,探讨ECP在COPD中的鉴别诊断价值及其与病情的相关关系。方法采用荧光酶免疫法检测53例COPD急性发作期患者、40例哮喘急性发作患者和39例健康对照的血清ECP。对结果进行对比分析。结果COPD患者ECP水平（48．09±31．33）μg／L明显高于健康对照组（7．83±3．65）μg／L而低于哮喘组（97．17±54．30）μg／L,差异均有统计学意义（P〈0．01）。通过ROC曲线分析,当ECP为66．85μg／L时,对COPD和哮喘的鉴别诊断具有最大灵敏度和特异度,分别为88．2％和88．6％。在COPD患者中,ECP水平随病情的加重而升高,重度和极重度患者的ECP水平明显高于中度患者（P〈0．05）,极重度患者的ECP水平与重度患者相比有增高趋势,但差异无统计学意义（P〉0．05）。结论cOPD患者ECP增高,且和疾病严重程度具有一定的相关性。C（）PD和哮喘在某些情况下症状极为相似,但COPD患者ECP的增高程度低于哮喘患者。因此,监测ECP水平对于COPD的诊断和鉴别诊断、病情监测、合理用药、评价抗炎治疗的效果有一定的参考价值。     

Fast clearing RGD‐based near‐infrared fluorescent probes for in vivo tumor diagnosis

A fast clearing hydrophilic near‐infrared (NIR) dye ICG‐Der‐02 was used to constitute tumor targeting contrast agents. Cell adhesion molecule integrin α_vβ₃ served as the target receptor because of its unique expression on almost all sprouting tumor vasculatures. The purpose of this study was to synthesize and compare the properties of integrin α_vβ₃‐targeted, fast clearing NIR probes both in vitro and in vivo for tumor diagnosis. ICG‐Der‐02 was covalently conjugated to three kinds of RGD peptide including linear, monoeric cyclic and dimeric RGD to form three RGD‐based NIR probes. The integrin receptor specificities of these probes were evaluated in vitro by confocal microscopy. The dynamic bio‐distribution and elimination ratse were in vivo real‐time monitored by a near‐infrared imaging system in normal mice. Further, the in vivo tumor targeting abilities of the RGD‐based NIR probes were compared in α_vβ₃‐positive MDA‐MB‐231, U87MG and α_vβ₃‐negtive MCF‐7 xenograft mice models. Three RGD‐based NIR probes were successfully synthesized with good optical properties. In vitro cellular experiments indicated that the probes have a clear binding affinity to α_υβ₃‐positive tumor cells, with a cyclic dimeric RGD probe owing the highest integrin affinity. Dynamic bio‐distributions of these probes showed a rapid clearing rate through the renal pathway. In vivo tumor targeting ability of the RGD‐based porbes was demonstrated on MDA‐MB‐231 and U87MG tumor models. As expected, the c(RGDyK)₂‐ICG‐Der‐02 probe displayed the highest tumor‐to‐normal tissue contrast. The in vitro and in vivo block experiments confirmed the receptor binding specificity of the probes. The hydrophilic dye‐labeled NIR probes exhibited a fast clearing rate and deep tissue penetration capability. Further, the α_υβ₃ receptor affinity of the three RGD‐based NIR probes followed the order of dimer cyclic > monomer cyclic > linear. The results demonstrate potent fast clearing probes for in vivo early tumor diagnosis. Copyright © 2012 John Wiley & Sons, Ltd.     

Withdrawal of inhaled steroids in children with non‐cystic fibrosis bronchiectasis

Background: To study the effects of inhaled steroid withdrawal on bronchial hyperreactivity, sputum inflammatory markers and neutrophilic apoptosis in children with non‐cystic fibrosis (non‐CF) bronchiectasis. Objectives: To evaluate the role of inhaled steroids in the treatment of children with non‐CF bronchiectasis with specific emphasis on the bronchial hyperreactivity and neutrophilic apoptosis. Methods: Twenty‐seven children with steady‐state non‐CF bronchiectasis were evaluated primarily with metacholine challenge tests and apoptotic neutrophil ratios in induced sputum and secondarily with symptom scores, pulmonary function tests and tumour necrosis factor‐alpha (TNF‐α), interleukin‐8 (IL‐8) levels and neutrophil ratios in induced sputum before and after 12‐week withdrawal of inhaled steroids. Results: There were 16 girls and 11 boys. Median (interquartile range) age was 11·4 (9·5–13·6) years, follow‐up duration was 3·5 (2–6·5) years. Symptom scores (4 vs. 3; P = 0·27), oxygen saturation (95% vs. 97%; P = 0·06), pulmonary function tests (FEV1: 82% predicted vs. 83% predicted; P = 0·73), sputum neutrophil ratios (29·9% vs. 46·8%; P = 0·20), TNF‐α (58 pg/mL vs. 44·5 pg/mL; P = 0·55) and IL‐8 (2·7 ng/mL vs. 2·4 ng/mL; P = 0·82) levels in induced sputum were similar before and after 12‐week withdrawal of inhaled steroids. However, the number of patients with bronchial hyperreactivity increased (37% vs. 63% of patients; P = 0·016) and neutrophilic apoptosis in induced sputum decreased (42·8% vs. 20·2%; P = 0·03) after withdrawal. Conclusion: In this study, 12 week‐withdrawal of inhaled steroid treatment resulted in a significant increase in bronchial hyperreactivity and decrease in neutrophil apoptosis, but no change in sputum inflammatory markers in children with non‐CF bronchiectasis was observed.