抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Chronic obstructive pulmonary disease (COPD) remains a major public health problem. It is the fourth leading cause of chronic morbidity and mortality in the United States, and is projected to rank fifth in 2020 in burden of disease worldwide, according to a study published by the World Bank/World Health Organization. Yet, COPD remains relatively unknown or ignored by the public as well as public health and government officials. In 1998, in an effort to bring more attention to COPD, its management, and its prevention, a committed group of scientists encouraged the U.S. National Heart, Lung, and Blood Institute and the World Health Organization to form the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Among the important objectives of GOLD are to increase awareness of COPD and to help the millions of people who suffer from this disease and die prematurely of it or its complications. The first step in the GOLD program was to prepare a consensus report, Global Strategy for the Diagnosis, Management, and Prevention of COPD, published in 2001. The present, newly revised document follows the same format as the original consensus report, but has been updated to reflect the many publications on COPD that have appeared. GOLD national leaders, a network of international experts, have initiated investigations of the causes and prevalence of COPD in their countries, and developed innovative approaches for the dissemination and implementation of COPD management guidelines. We appreciate the enormous amount of work the GOLD national leaders have done on behalf of their patients with COPD. Despite the achievements in the 5 years since the GOLD report was originally published, considerable additional work is ahead of us if we are to control this major public health problem. The GOLD initiative will continue to bring COPD to the attention of governments, public health officials, health care workers, and the general public, but a concerted effort by all involved in health care will be necessary.

https://www.who.int/respiratory/copd/GOLD_WR_06.pdf

Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.

Global strategy for asthma management and prevention

Probability Distributions.- Linear Models for Regression.- Linear Models for Classification.- Neural Networks.- Kernel Methods.- Sparse Kernel Machines.- Graphical Models.- Mixture Models and EM.- Approximate Inference.- Sampling Methods.- Continuous Latent Variables.- Sequential Data.- Combining Models.

Pattern Recognition and Machine Learning

The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stressresponse or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole. (Endocrine Reviews 21: 55‐ 89, 2000)

/pdf/how-do-glucocorticoids-influence-stress-responses-4egr3fa2k0.pdf

How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

We investigated the effect of Ba 679 BR, a novel long-acting antimuscarinic agent, on cholinergic neural responses in guinea pig and human airways. Ba 679 BR, atropine, and ipratropium bromide inhibited electrical field stimulation (EFS)-induced contraction with IC50 values of 0.17, 0.74, and 0.58 nM, respectively, in guinea pig trachea. Ba 679 BR had a slower onset and longer duration of action than atropine or ipratropium bromide (the times required to attain 50% of the maximum response were 34.8, 3.8, and 7.6 min, respectively, and the times required for 50% recovery of the response were 540, 31.6, and 81.2 min, respectively). Ba 679 BR, as well as atropine and ipratropium bromide, facilitated evoked [3H]acetylcholine release (an inhibitory effect on prejunctional muscarinic M2 receptors). The facilitation of acetylcholine release by Ba 679 BR was lost 2 h after washout, however, when there was still complete blockade of cholinergic contractile responses evoked by EFS (an effect on airway smooth muscle...

Effect of Ba 679 BR, a novel long-acting anticholinergic agent, on cholinergic neurotransmission in guinea pig and human airways.

Background: Leukotriene-like immunoreactivity has been detected in exhaled breath condensate (EBC), but definitive evidence for the presence of leukotrienes (LTs) in this biological fluid is not available. A study was undertaken to determine whether LTC4, LTD4, LTE4, and LTB4 are measurable in EBC by gas chromatography/mass spectrometry and to quantify exhaled LTs in adults and children with asthma and in control subjects. 

Methods: Twenty eight adults and 33 children with mild to moderate persistent asthma treated with inhaled corticosteroids and age matched healthy controls (50 adults and 50 children) were studied. LTB4, LTC4, LTD4, and LTE4 in EBC were measured by gas chromatography/mass spectrometry. 

Results: LTD4, LTE4, and LTB4 were detectable in all samples. Concentrations of LTC4 in EBC were either close to or below the detection limit of 1 pg/ml. Median exhaled LTD4, LTE4, and LTB4 concentrations in asthmatic adults were increased 4.1-fold (p<0.001), 1.8-fold (p<0.01), and 2.6-fold (p<0.001), respectively, compared with values in healthy adults. Median exhaled LTD4, LTE4, and LTB4 concentrations in asthmatic children were increased 2.8-fold (p<0.001), 1.3-fold (p<0.001), and 1.6-fold (p<0.001), respectively, compared with those in healthy children. In patients with asthma there was a correlation between exhaled LTD4 and LTE4 in both adults (r = 0.87, p<0.0001) and children (r = 0.78, p<0.0001). 

Conclusions: Gas chromatography/mass spectrometry can be used to accurately quantify exhaled LTs which are increased in asthmatic adults and children compared with controls.

https://thorax.bmj.com/content/thoraxjnl/59/6/465.full.pdf

Gas chromatography/mass spectrometry analysis of exhaled leukotrienes in asthmatic patients

Nitric oxide (NO), a simple free-radical gas, elicits a diverse range of physiologic and pathophysiologic effects, and plays an important role in pulmonary diseases. Nitrosative stress and nitration of proteins in airway epithelium may be responsible for steroid resistance in asthma and their ineffectiveness in chronic obstructive pulmonary disease (COPD), supporting the potential role of future therapeutic strategies aimed at regulating NO synthesis in asthma and COPD. In this article, we review the potential role of NO modulators (NO synthase inhibitors and NO donors), which, if given on a regular basis, may have clinical benefit in asthma and COPD.

Nitric oxide, nitrotyrosine, and nitric oxide modulators in asthma and chronic obstructive pulmonary disease

Eosinophils (EOS) may play an important role in the pathophysiology of bronchial asthma because they can release oxygen free radicals and several basic proteins which are cytotoxic to bronchial epithelium. We have studied the response of EOS isolated from the blood of atopic subjects with symptoms of asthma (AS, n = 7) or rhinitis (AR, n = 4) or without symptoms (AA, n = 5) and of subjects with the hypereosinophilic syndrome (HES, n = 5). EOS were separated using metrizamide density gradients and activated in vitro with platelet-activating factor (PAF, 100 nM) or phorbol 12-myristate-13-acetate (PMA, 100 nM). Oxygen free radical generation was assessed by a lucigenin-enhanced chemiluminescence (CL) assay. EOS purity was 83 +/- 1.7% (mean +/- SEM) with greater than 95% viability. Background CL responses of EOS from HES were significantly higher than those from AA (p less than 0.01) and AR (p less than 0.05). Normodense EOS from AS (PAF-induced CL = 90 +/- 27 mV) were more responsive to PAF than were those from AR (17 +/- 13 mV, p less than 0.01) and from AA (23 +/- 14 mV, p less than 0.01). Similar results were obtained with PMA. Hypodense EOS from HES subjects were as responsive as normodense EOS from AS to PMA and PFA. Thus, EOS from AS have an enhanced potential for activation, particularly by PAF; this may represent an important mechanism for the perpetuation of the inflammatory response in asthma, since EOS can also release PAF.

https://erj.ersjournals.com/content/erj/3/9/1002.full.pdf

Generation of oxygen free radicals from blood eosinophils from asthma patients after stimulation with PAF or phorbol ester.

"The Second Edition of Asthma and COPD: Basic Mechanisms and Clinical Management" continues to provide a unique and authoritative comparison of asthma and COPD. Written and edited by the world's leading experts, it continues to be a comprehensive review of the most recent understanding of the basic mechanisms of both conditions, specifically comparing their etiology, pathogenesis, and treatments. Each chapter considers Asthma and COPD in side-by-side contrast and comparison not in isolation - in the context of mechanism, triggers, assessments, therapies, and clinical management. This title presents the latest and most comprehensive understandings of the mechanisms of inflammation in both Asthma and COPD. It provides most extensive reference to primary literature on both Asthma and COPD in one source. It offers easy-to-read summaries of the latest advances alongside clear illustrations.

Peter J. Barnes

Papers

Effect of Ba 679 BR, a novel long-acting anticholinergic agent, on cholinergic neurotransmission in guinea pig and human airways.

Gas chromatography/mass spectrometry analysis of exhaled leukotrienes in asthmatic patients

Nitric oxide, nitrotyrosine, and nitric oxide modulators in asthma and chronic obstructive pulmonary disease

Generation of oxygen free radicals from blood eosinophils from asthma patients after stimulation with PAF or phorbol ester.

Asthma and COPD : Basic Mechanisms and Clinical Management