Hyaluronan and Its Heavy Chain Modification in Asthma Severity and Experimental Asthma Exacerbation

Hyaluronan (HA) is a large (>1500 kDa) polysaccharide of the extracellular matrix that has been linked to severity and inflammation in asthma. During inflammation, HA becomes covalently modified with heavy chains (HC-HA) from inter-α-inhibitor (IαI), which functions to increase its avidity for leukocytes. Our murine model of allergic pulmonary inflammation suggested that HC-HA may contribute to inflammation, adversely effecting lower airway remodeling and asthma severity. Our objective was to characterize the levels of HA and HC-HA in asthmatic subjects and to correlate these levels with asthma severity. We determined the levels and distribution of HA and HC-HA (i) from asthmatic and control lung tissue, (ii) in bronchoalveolar lavage fluid obtained from non-severe and severe asthmatics and controls, and (iii) in serum and urine from atopic asthmatics after an experimental asthma exacerbation. HC-HA distribution was observed (i) in the thickened basement membrane of asthmatic lower airways, (ii) around smooth muscle cells of the asthmatic submucosa, and (iii) around reserve cells of the asthmatic epithelium. Patients with severe asthma had increased HA levels in bronchoalveolar lavage fluid that correlated with pulmonary function and nitric oxide levels, whereas HC-HA was only observed in a patient with non-severe asthma. After an experimental asthma exacerbation, serum HA was increased within 4 h after challenge and remained elevated through 5 days after challenge. Urine HA and HC-HA were not significantly different. These data implicate HA and HC-HA in the pathogenesis of asthma severity that may occur in part due to repetitive asthma exacerbations over the course of the disease.     

Enhancing Personal Wellness in Counselor Trainees Using Biofeedback: An Exploratory Study

The purpose of this study was to explore whether biofeedback-assisted relaxation training could reduce stress-related symptoms and enhance personal well-being in a group of counselor trainees enrolled in a basic counseling skills course. Treatment participants received ten sessions of weekly biofeedback-assisted relaxation training, whereas the control participants received no intervention. The treatment group showed, significant improvements in several symptom areas measured by the Symptom Checklist 90-Revised: physical complaints (Somatization), personal inadequacy (Interpersonal Sensitivity), confused thinking or alienation or both (Psychoticism), and the overall number and severity of symptoms (Global Severity Index and Positive Symptom Total). The control participants showed no significant improvements in any symptom areas. Biofeedback-assisted relaxation was shown to be an effective stress-reducing intervention for counselor trainees, which resulted in a greater sense of personal well-being.     

Long-term effects of biofeedback-induced facial relaxation on measures of asthma severity in children

We studied the effects of electromyographic biofeedback on measures of asthma severity in children. Fifteen children received biofeedback training to reduce facial tension, and 14 children, who served as controls, received biofeedback training to maintain facial tension at a stable level. Assignment to experimental condition was random. As a result of training, electromyographic levels decreased in children trained in facial relaxation and remained fairly constant in children trained in facial tension stability. Biofeedback training was augmented for children in both groups by having them practice their facial exercises at home. Each child's condition was followed for a five-month period subsequent to biofeedback training. Throughout the experiment, the following measures of asthma severity were monitored: lung function, self-rated asthma severity, medication usage, and frequency of asthma attacks. In addition, standardized measures of attitudes toward asthma, self-concept, and chronic anxiety were recorded at regular intervals. As compared to the facial stability subjects, the facial relaxation subjects exhibited higher pulmonary scores, more positive attitudes toward asthma, and lower chronic anxiety during the follow-up period. Subjects in the two groups, however, did not differ on self-rated asthma severity, medication usage, frequency of asthma attacks, or self-concept. Based on the improvements we observed in pulmonary, attitude, and anxiety measures, we concluded that biofeedback training for facial relaxation contributes to the self-control of asthma and would be a valuable addition to asthma self-management programs.     

Behavioral strategies for the reduction of pain and anxiety associated with orthopedic trauma

This study examined the efficacy of behavioral strategies in alleviating pain and anxiety associated with severe orthopedic trauma. Sixty-four patients with multiple fractures were divided into four groups: (1) control, (2) attention only, (3) EMG biofeedback-assisted relaxation, and (4) audiotaped relaxation training. All were measured over at least six sessions, or as long as hospital stay permitted. Significant between group differences were found on the following: systolic blood pressure, pheripheral temperature, subjective units of discomfort, state anxiety, with a trend for use of sleep medications. No differences were found on other vital signs, EMG recordings, or other medications. EMG-biofeedback relaxation and relaxation training were relatively equivalent for all measures, and little or no change was observed for those patients who received attention only or served as controls.     

Long-term effects of biofeedback-induced facial relaxation on measures of asthma severity in children

We studied the effects of electromyographic biofeedback on measures of asthma severity in children. Fifteen children received biofeedback training to reduce facial tension, and 14 children, who served as controls, received biofeedback training to maintain facial tension at a stable level. Assignment to experimental condition was random. As a result of training, electromyographic levels decreased in children trained in facial relaxation and remained fairly constant in children trained in facial tension stability. Biofeedback training was augmented for children in both groups by having them practice their facial exercises at home. Each child's condition was followed for a five-month period subsequent to biofeedback training. Throughout the experiment, the following measures of asthma severity were monitored: lung function, self-rated asthma severity, medication usage, and frequency of asthma attacks. In addition, standardized measures of attitudes toward asthma, self-concept, and chronic anxiety were recorded at regular intervals. As compared to the facial stability subjects, the facial relaxation subjects exhibited higher pulmonary scores, more positive attitudes toward asthma, and lower chronic anxiety during the followup period. Subjects in the two groups, however, did not differ on self-rated asthma severity, medication usage, frequency of asthma attacks, or self-concept. Based on the improvements we observed in pulmonary, attitude, and anxiety measures, we concluded that biofeedback training for facial relaxation contributes to the self-control of asthma and would be a valuable addition to asthma self-management programs.This research was supported by NIH grant No. HL27402. We are grateful to Anita D. Baker, Lisa Barclay, Deborah L. Harm, and Douglas J. Miller for serving as experimenters and to Constance K. Cottrell and Cindy Stout for compiling summaries of the data.     

Behavioral strategies for the reduction of pain and anxiety associated with orthopedic trauma

This study examined the efficacy of behavioral strategies in alleviating pain and anxiety associated with severe orthopedic trauma. Sixty-four patients with multiple fractures were divided into four groups: (1) control, (2) attention only, (3) EMG biofeedback-assisted relaxation, and (4) audiotaped relaxation training. All were measured over at least six sessions, or as long as hospital stay permitted. Significant between group differences were found on the following: systolic blood pressure, peripheral temperature, subjective units of discomfort, state anxiety, with a trend for use of sleep medications. No differences were found on other vital signs, EMG recordings, or other medications. EMG-biofeedback relaxation and relaxation training were relatively equivalent for all measures, and little or no change was observed for those patients who received attention only or served as controls.     

Vitamin D receptor expression by the lung micro-environment is required for maximal induction of lung inflammation

Mice lacking the vitamin D receptor (VDR) are resistant to airway inflammation. Pathogenic immune cells capable of transferring experimental airway inflammation to wildtype (WT) mice are present and primed in the VDR KO mice. Furthermore, the VDR KO immune cells homed to the WT lung in sufficient numbers to induce symptoms of asthma. Conversely, WT splenocytes, Th2 cells and hematopoetic cells induced some symptoms of experimental asthma when transferred to VDR KO mice, but the severity was less than that seen in the WT controls. Interestingly, experimentally induced vitamin D deficiency failed to mirror the VDR KO phenotype suggesting there might be a difference between absence of the ligand and VDR deficiency. Lipopolysaccharide (LPS) induced inflammation in the lungs of VDR KO mice was also less than in WT mice. Together the data suggest that vitamin D and the VDR are important regulators of inflammation in the lung and that in the absence of the VDR the lung environment, independent of immune cells, is less responsive to environmental challenges.     

布地奈德联合孟鲁司特钠对支气管哮喘患儿细胞因子、免疫功能影响

目的:探讨布地奈德联合孟鲁司特钠对支气管哮喘患儿细胞因子、免疫功能影响。方法:选自我院于2014年9月~2016年3月期间收治的支气管哮喘患儿96例,依据随机数字表法随机分为观察组与对照组,每组48例。对照组给予孟鲁司特钠治疗,观察组在对照组基础上结合布地奈德治疗。两组疗程均为4周。观察并比较两组的临床疗效、以及治疗前后患者血清细胞因子水平、免疫功能及肺功能的变化情况。结果:观察组治疗总有效率(95.83%)高于对照组(79.17%)(P0.05);观察组血清IL-5含量治疗后低于对照组,而IL-12含量高于对照组(P0.05);观察组血清Ig E含量治疗后低于对照组,而Ig A、Ig M含量高于对照组(P0.05);观察组FEV1和FVC治疗后高于对照组(P0.05);两组均未见明显不良反应。结论:布地奈德联合孟鲁司特钠治疗支气管哮喘患儿疗效显著,且作用可能与改善细胞因子、免疫功能及肺功能有关。     

Change of Cu,Zn-superoxide Dismutase Activity of Guinea Pig Lung in Experimental Asthma

Correlation between the level of reactive oxygen species (ROS) generated by airway inflammatory cells and superoxide dismutase (SOD) activity of pulmonary tissue during an asthma attach was investigated in a guinea pig model of allergic asthma. In addition, the influence of SOD inhibition by diethyldithiocarbamate (DDC, Cu-chelating agent) on the airway was investigated in terms of pulmonary function during an asthma attach. Relative to controls, the capacity of bronchoalveolar lavage fluid (BAL) cells to release ROS was significantly increased in guinea pigs sensitized with ovalbumin (OA) as the antigen, and significantly increased in guinea pigs with an asthma attack provoked by the inhalation of OA. SOD activity was increased significantly in the antigen-sensitized group. The asthma provocation group showed a tendency for increase in total SOD activity, compared with the sensitization group, whose increase was dependent on the increase in copper, zinc-SOD (Cu, Zn-SOD) activity. Pretreatment with DDC increased the severity and duration of the asthma attack. These results were indicated that Cu, Zn-SOD was closely involved in the asthma process, particularly in the scavenging of oxygen radicals secreted from BAL cells.     

Behavioral Inhibition in Rhesus Monkeys (Macaca mulatta) Is Related to the Airways Response,but Not Immune Measures,Commonly Associated with Asthma

Behavioral inhibition reflects a disposition to react warily to novel situations, and has been associated with atopic diseases such as asthma. Retrospective work established the relationship between behavioral inhibition in rhesus monkeys (Macaca mulatta) and airway hyperresponsiveness, but not atopy, and the suggestion was made that behavioral inhibition might index components of asthma that are not immune-related. In the present study, we prospectively examined the relationship between behavioral inhibition and airway hyperresponsiveness, and whether hormonal and immune measures often associated with asthma were associated with behavioral inhibition and/or airway hyperresponsiveness. In a sample of 49 yearling rhesus monkeys (mean = 1.25 years, n = 24 behaviorally inhibited animals), we measured in vitro cytokine levels (IL-4, IL-10, IL-12, IFN-γ) in response to stimulation, as well as peripheral blood cell percentages, cortisol levels, and percentage of regulatory T-cells (CD3+CD4+CD25+FOXP3+). Airway reactivity was assessed using an inhaled methacholine challenge. Bronchoalveolar lavage was performed and the proportion of immune cells was determined. Behaviorally inhibited monkeys had airway hyperresponsiveness as indicated by the methacholine challenge (p = 0.031), confirming our earlier retrospective result. Airway hyperresponsiveness was also associated with lower lymphocyte percentages in lavage fluid and marginally lower plasma cortisol concentrations. However, none of the tested measures was significantly related to both behavioral inhibition and airway hyperresponsiveness, and so could not mediate their relationship. Airway hyperresponsiveness is common to atopic and non-atopic asthma and behavioral inhibition has been related to altered autonomic activity in other studies. Our results suggest that behavioral inhibition might index an autonomically mediated reactive airway phenotype, and that a variety of stimuli (including inflammation within lung tissue that is not specifically associated with behavioral inhibition) may trigger the airways response.     

Total and specific serum IgE decreases with age in patients with allergic rhinitis,asthma and insect allergy but not in patients with atopic dermatitis

Concerning allergic diseases, the incidence of allergic symptoms, as well as their severity, seems to decrease with age. The decline of onset of allergic symptoms observed in ageing might result from a decrease of serum total and specific IgE. Atopic disorders are complex diseases that involve interactions among several physiological systems, e.g. skin, lung, mucosae, and the immune system. It was the aim of this study to compare the effects of age on total and specific IgE in patients with atopic dermatitis (AD), allergic rhinitis or asthma, and insect allergy, respectively.     

The anergic state in sarcoidosis is associated with diminished dendritic cell function

Sarcoidosis is a chronic inflammatory disease of unknown cause, characterized by granuloma formation similar to tuberculosis, but without clear evidence of a microbial infection. Because sarcoidosis is linked with clinical anergy and other evidence of diminished cellular immunity, we hypothesized that decreased skin delayed-type hypersensitivity (DTH) responses to recall Ags in affected individuals would be associated with decreased function of their blood dendritic cells (DCs). Our study involved ex vivo isolation, phenotyping, and functional testing of myeloid DCs (mDCs), plasmacytoid DCs, and T lymphocytes from blood of normal healthy volunteers and sarcoidosis subjects with active, untreated pulmonary disease. We found mDC function in the allogeneic MLR directly corresponded to the magnitude of skin DTH reactions to recall Ags in both sarcoidosis subjects and normal volunteers. However, both of these outcomes were significantly decreased in the sarcoidosis group. Diminished mDC function occurred despite up-regulated costimulatory and maturation markers. Clinical relevance is suggested by the inverse relationship between both mDC allogeneic responses and skin DTH responses with clinical disease severity as measured by chest radiograms. Because granulomas form when cellular immunity fails to clear antigenic stimuli, attenuated mDC function in sarcoidosis may contribute to susceptibility and persistence of the chronic inflammation characteristic of this disease.     

Sustained effects of biofeedback-assisted relaxation therapy in essential hypertension

The usefulness of biofeedback-assisted relaxation as an adjunct or substitute for pharmacotherapy in essential hypertension can be enhanced if the effects are shown to persist after formal treatment has ended. Patients with essential hypertension successfully treated with biofeedback-assisted relaxation were recalled for follow-up yearly after the termination of treatment. Twenty-six of 40 patients met the BP criterion for success. At one-, two-, and three-year follow-up, 31%, 38%, and 27% of the successful completers continued to meet the criterion for success. The pretreatment-posttreatment decreases in BP were accompanied by decreases in forehead muscle tension and urinary cortisol. Forehead muscle tension, urinary cortisol, and anxiety levels were significantly lower than pretreatment one year after the end of treatment. Self-report data were used to assess continued relaxation practice. No relationship was found between practice and any other dependent measure. It appears that some patients trained in biofeedback-assisted relaxation can maintain lowered blood pressure, muscle tension, anxiety, and cortisol levels over the long term; however, the role of relaxation practice in maintaining these lowered levels remains unclear.     

Sustained effects of biofeedback-assisted relaxation therapy in essential hypertension.

The usefulness of biofeedback-assisted relaxation as an adjunct or substitute for pharmacotherapy in essential hypertension can be enhanced if the effects are shown to persist after formal treatment has ended. Patients with essential hypertension successfully treated with biofeedback-assisted relaxation were recalled for follow-up yearly after the termination of treatment. Twenty-six of 40 patients met the BP criterion for success. At one-, two-, and three-year follow-up, 31%, 38%, and 27% of the successful completers continued to meet the criterion for success. The pretreatment-posttreatment decreases in BP were accompanied by decreases in forehead muscle tension and urinary cortisol. Forehead muscle tension, urinary cortisol, and anxiety levels were significantly lower than pretreatment one year after the end of treatment. Self-report data were used to assess continued relaxation practice. No relationship was found between practice and any other dependent measure. It appears that some patients trained in biofeedback-assisted relaxation can maintain lowered blood pressure, muscle tension, anxiety, and cortisol levels over the long term; however, the role of relaxation practice in maintaining these lowered levels remains unclear.     

Interaction of biofeedback-assisted relaxation and diuretic in treatment of essential hypertension.

Thirty patients with essential hypertension participated in a study designed to compare two treatments: diuretic medication alone (n = 10) and biofeedback assisted relaxation combined with diuretic (n = 20). One of 10 patients lowered BP with diuretic alone and 11 of 20 patients lowered BP with diuretic combined with biofeedback-assisted relaxation. The addition of the behavioral intervention to the diuretic therapy produced a decrease in blood pressure beyond that associated with the diuretic alone. The decrease in BP mediated by diuretic were related to high entry levels of BP, low anxiety, forehead muscle tension, anger expression and plasma renin activity. The BP decrease mediated by combined diuretic and biofeedback-assisted relaxation was associated with high pretreatment BP, anger controlled, low finger temperature and high/normal plasma renin activity.     

Toll-Like Receptor Ligands LPS and Poly (I:C) Exacerbate Airway Hyperresponsiveness in a Model of Airway Allergy in Mice,Independently of Inflammation

It is well-established that bacterial and viral infections have an exacerbating effect on allergic asthma, particularly aggravating respiratory symptoms, such as airway hyperresponsiveness (AHR). The mechanism by which these infections alter AHR is unclear, but some studies suggest that Toll-like receptors (TLRs) play a role. In this study, we investigated the impact of TLR3 and TLR4 ligands on AHR and airway inflammation in a model of pre-established allergic inflammation. Female BALB/c mice were sensitised and challenged intranasally (i.n.) with either PBS or ovalbumin (OVA) and subsequently i.n. challenged with poly (I:C) (TLR3) or LPS (TLR4) for four consecutive days. The response to methacholine was measured in vivo; cellular and inflammatory mediators were measured in blood, lung tissue and broncheoalveolar lavage fluid (BALF). OVA challenge resulted in an increase in AHR to methacholine, as well as increased airway eosinophilia and TH2 cytokine production. Subsequent challenge with TLR agonists resulted in a significant increase in AHR, but decreased TLR-specific cellular inflammation and production of immune mediators. Particularly evident was a decline in LPS-induced neutrophilia and neutrophil-associated cytokines following LPS and poly (I:C) treatment. The present data indicates that TLRs may play a pivotal role in AHR in response to microbial infection in allergic lung inflammation. These data also demonstrate that aggravated AHR occurs in the absence of an exacerbation in airway inflammation and that allergic inflammation impedes a subsequent inflammatory response to TLRs. These results may parallel clinical signs of microbial asthma exacerbation, including an extended duration of illness and increased respiratory symptoms.     

Focus: Microbiome: Breathing Better Through Bugs: Asthma and the Microbiome

Asthma is a highly heterogeneous disease characterized by inflammation of the airways, which invokes symptoms such as wheeze, dyspnea, and chest tightness. Asthma is the product of multiple interconnected immunological processes and represents a constellation of related, but distinct, disease phenotypes. The prevalence of asthma has more than doubled since the 1980s, and efforts to understand this increase have inspired consideration of the microbiome as a key player in the pathophysiology and regulation of this disease. While recent years have seen an explosion of new research in this area, researchers are only beginning to untangle to mechanisms by which the microbiome may influence asthma. This review will focus on the relationship between the microbiome and the immune system and how this influences development of asthma. This review will also highlight evidence that may point the way toward new therapies and potential cures for this ancient respiratory foe.     

Obstructive Sleep Apnoea Modulates Airway Inflammation and Remodelling in Severe Asthma

Background

Obstructive sleep apnoea (OSA) is frequently observed in severe asthma but the causal link between the 2 diseases remains hypothetical. The role of OSA-related systemic and airway neutrophilic inflammation in asthma bronchial inflammation or remodelling has been rarely investigated. The aim of this study was to compare hallmarks of inflammation in induced sputum and features of airway remodelling in bronchial biopsies from adult patients with severe asthma with and without OSA.

Materials and Methods

An overnight polygraphy was performed in 55 patients referred for difficult-to-treat asthma, who complained of nocturnal respiratory symptoms, poor sleep quality or fatigue. We compared sputum analysis, reticular basement membrane (RBM) thickness, smooth muscle area, vascular density and inflammatory cell infiltration in bronchial biopsies.

Results

In total, 27/55 patients (49%) had OSA diagnosed by overnight polygraphy. Despite a moderate increase in apnoea-hypopnoea index (AHI; 14.2±1.6 event/h [5–35]), the proportion of sputum neutrophils was higher and that of macrophages lower in OSA than non-OSA patients, with higher levels of interleukin 8 and matrix metalloproteinase 9. The RBM was significantly thinner in OSA than non-OSA patients (5.8±0.4 vs. 7.8±0.4 μm, p<0.05). RBM thickness and OSA severity assessed by the AHI were negatively correlated (rho = -0.65, p<0.05). OSA and non-OSA patients did not differ in age, sex, BMI, lung function, asthma control findings or treatment.

Conclusion

Mild OSA in patients with severe asthma is associated with increased proportion of neutrophils in sputum and changes in airway remodelling.     

Biofeedback-assisted relaxation training for primary dysmenorrhea: a case study.

Primary dysmenorrhea is a familiar complaint to medical practitioners. Recently, behavior therapy has been shown to be an effective treatment for the symptoms of dysmenorrhea. The present case study offers biofeedback-assisted relaxation treatment as an effective alternative treatment. The Menstrual Symptom Questionnaire was used to classify dysmenorrhea as spasmodic or congestive. This classification provides homogeneous groups of patients. The patient in this study had an 18-year history of primary dysmenorrhea that was resistant to hormonal and analgesic treatment. After two months of baseline observation, she was given eight sessions of skin-temperature biofeedback and autogenic training. She reported significant reduction of pain and discomfort with the use of biofeedback-assisted relaxation. Desensitization using visual imagery, an important component of previous therapies, was not used. Further examination of the efficacy of biofeedback-assisted relaxation training for the treatment of both congestive and spasmodic dysmenorrhea is suggested.     

Game-based biofeedback for paediatric anxiety and depression

Twenty-four children and adolescents aged 9-17 who were referred for treatment for anxiety were assigned to either a game-based biofeedback group or a waiting list comparison group. The eight-session biofeedback intervention included psychoeducation, identification of triggers and signs of anxiety, and in vivo practice. The intervention used computer-based gaming technology to teach and practise relaxation. Analyses using ANCOVA revealed significant differences in post-test scores of anxiety and depression measures between the two groups. The intervention group reduced anxiety and depression scores on standardised tests. Findings suggest that biofeedback-assisted relaxation training can be useful in decreasing anxiety and depressive symptoms in anxious youths.