Structural and functional organization of the hemostatic clot

Experimental data confirming the authors' hypothesis relating to structural and functional organization of the hemostatic clot are described. The basis of the clot is a fibrin-platelet structure in the meshes of which erythrocytes and leukocytes are distributed. Spontaneous compaction of the clot (retraction) takes place on account of the contractile properties of the surface structure of the activated platelets-extruded platelet cytogel. It is demonstrated that disturbance of the structure of the clot during aggregation of the platelets leads to inhibition of retraction. The sequence of processes taking place during formation and contraction of the clot is discussed.Laboratory of Thromboresistant Materials, Institute of Transplantation of Organs and Tissues, Ministry of Health of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR V. S. Savel'ev.) Translated from Byulleten' Éksperimental'nol Biologii i Meditsiny, Vol. 85, No. 2, pp. 132–136, February, 1978.     

Mediterranean diet is associated with reduced asthma and rhinitis in Mexican children

Background: Diet during pregnancy and childhood has been suggested to play an important role in children’s asthma risk. We assessed whether the adherence to a Mediterranean dietary pattern, for children in the last 12 months and their mothers during pregnancy, was associated with both childhood asthma and allergic rhinitis. Methods: A cross‐sectional study was conducted in 2004 using a random sample of 1476 children (6‐ to 7‐year old) from the Mexicali region, Mexico. Dietary data of children’s intake in the last 12 months and their mothers’ intake during pregnancy was collected, through a parental food frequency questionnaire. A Mediterranean diet score was computed [Trichopoulou et al., N Engl J Med 348 (2003), 2599]. Data on seven asthma and rhinitis‐related outcomes were obtained from the International Study of Asthma and Allergies in Childhood questionnaire. Results: Adherence to a Mediterranean dietary pattern was inversely associated with asthma ever (OR = 0.60, 95% CI = 0.40–0.91), wheezing ever (0.64, 0.47–0.87), rhinitis ever (0.41, 0.22–0.77), sneezing ever (0.79, 0.59–1.07), current sneezing (0.71, 0.52–0.96) and current itchy‐watery eyes (0.63, 0.42–0.95). No associations were found using the mothers’ pregnancy diet score, except for current sneezing (0.71, 0.53–0.97). Conclusions: Our findings suggest a protective effect of following a healthy dietary pattern on asthma and allergic rhinitis in Mexican children.     

Asthma is associated with single-nucleotide polymorphisms in ADAM33

BACKGROUND : The ADAM33 gene has recently been associated with asthma and bronchial hyper-reactivity. It codes for a disintegrin and metalloproteinase that triggers intra- and extracellular signalling by protein shedding. OBJECTIVE : We examined whether polymorphisms in ADAM33 are associated with asthma and related traits in two German populations. METHODS : We genotyped 15 intragenic single-nucleotide polymorphisms (SNPs) by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of allele-specific primer extension products. The transmission disequilibrium test was used for association analysis in the German asthma family study. Additionally, we tested for association of these SNPs in a case-control sample from the European Community Respiratory Health Study using Armitage's trend test. RESULTS : In both studies, we found SNPs that were significantly associated with asthma and related traits. In the family study, significant associations were observed for the SNPs F+1, ST+4 and ST+5 (with the lowest P-value for F+1, P=0.005). Remarkably, this association is seen even in the absence of linkage with two microsatellite markers from a previous genome scan either 3.1 million bases (Mb) up- or 5.6 Mb downstream. In the case-control study, SNP ST+7 (P=0.008) was significantly associated with asthma. Some of these SNPs overlapped with those found to be associated with elevated total IgE levels and bronchial hyper-responsiveness. CONCLUSION : This study replicates the recently published association between asthma and ADAM33 gene variants. However, most of the associated SNPs were at non-identical positions in the German, UK and US samples. As linkage disequilibrium is high among the tested SNPs, and there is no known functional polymorphism, either not-tested variants in ADAM33, unknown regulatory elements or a gene in close proximity is responsible for this association.     

Omalizumab therapy is associated with reduced circulating basophil populations in asthmatic children

Basophils have been implicated in promoting the early development of T_H2 cell responses in some murine models of T_H2 cytokine‐associated inflammation. However, the specific role of basophils in allergic asthma remains an active area of research. Recent studies in animal models and human subjects suggest that IgE may regulate the homeostasis of human basophil populations. Here, we examine basophil populations in children with severe asthma before and during therapy with the IgE‐directed monoclonal antibody omalizumab. Omalizumab therapy was associated with a significant reduction in circulating basophil numbers, a finding that was concurrent with improved clinical outcomes. The observation that circulating basophils are reduced following omalizumab therapy supports a mechanistic link between IgE levels and circulating basophil populations, and may provide new insights into one mechanism by which omalizumab improves asthma symptoms.     

Allergen-induced bronchial inflammation is associated with decreased levels of surfactant proteins A and D in a murine model of asthma

Background Increasing evidence suggests that pulmonary surfactant protein A (SP‐A) and D (SP‐D) participate in the lung defence against pathogens. However, the role of surfactant proteins in the pathogenesis of allergen‐induced airway inflammation has not been elucidated. In this study we examined the levels and distributions of SP‐A and SP‐D in a dust mite (Dermatophagoides pteronyssinus, Der p) allergen‐induced murine model of asthma. Methods The concentration of SP‐A and SP‐D in the bronchoalveolar lavage fluid (BALF) and the distribution of surfactant proteins in the lung were assayed by ELISA and immunohistochemistry methods, respectively. The effect of surfactant proteins on allergen‐induced pulmonary lymphocyte proliferation was also studied. Results We demonstrated that there were marked reductions of SP‐A and SP‐D levels in the BALF of Der p‐sensitized BALB/c mice at 48–72 h after allergen challenge (AC). Both purified SP‐A and SP‐D were able to suppress, in a dose dependent manner, Der p‐stimulated intrapulmonary lymphocyte proliferation of naïve mice with saline or allergen challenge, or of Der p‐sensitized mice with saline challenge. On the contrary, this suppressive effect was mild (< 9%) on lymphocytes from sensitized mice after AC. Conclusion These results indicated the involvement of pulmonary surfactant proteins in the allergic bronchial inflammation of sensitized mice.     

信必可都保联合噻托溴铵治疗对COPD合并支气管哮喘患者肺功能、免疫功能及气道阻力的影响

目的研究信必可都保联合噻托溴铵治疗对慢性阻塞性肺疾病(COPD)合并支气管哮喘患者肺功能、免疫功能及气道阻力的影响。方法选取88例COPD合并支气管哮喘患者,随机分成两组,每组各44例,对照组噻托溴铵治疗,观察组信必可都保+噻托溴铵治疗,两组疗程均为2周,比较两组肺功能、免疫功能及气道阻力。结果治疗后,观察组总有效率为93.18%,明显高于对照组的77.26%(P<0.05);两组哮喘控制测试(ACT)评分较治疗前明显升高(P<0.05),且观察组升高幅度大于对照组(P <0.05);两组第1秒最大呼气量(FEV1.0)、第1秒最大呼气率(FEV1.0%)、最大呼气流速峰值(PEFR)、肺活量(FVC)较治疗前明显升高(P<0.05),两组肺动脉收缩压(PASP)、肺动脉舒张压(PADP)、平均肺动脉压(MPAP)较治疗前明显降低(P <0.05),且观察组变化幅度大于对照组(P <0.05);两组CD4^+、CD4^+/CD8^+、免疫球蛋白A(IgA)、免疫球蛋白G(IgG)、免疫球蛋白M(IgM)较治疗前明显升高(P<0.05),两组CD8^+较治疗前明显降低(P<0.05),且观察组变化幅度大于对照组(P <0.05);两组气道总阻抗(Z5)、气道总粘性阻力(R5)、近端气道粘性阻力(R20)、周边弹性阻力(X5)较治疗前明显降低(P<0.05),且观察组降低幅度大于对照组(P <0.05);两组血管内皮生长因子(VEGF)、细胞间黏附分子(ICAM-1)、白细胞介素-13(IL-13)、白细胞介素-17(IL-17)较治疗前明显降低(P<0.05),且观察组降低幅度大于对照组(P<0.05);两组在治疗期间未出现明显不良反应。结论信必可都保联合噻托溴铵治疗COPD合并支气管哮喘疗效显著,有效改善肺功能和哮喘情况,调节免疫功能、降低气道阻力和诱导痰细胞因子水平,安全性好,值得临床推广。     

The LPL S447X cSNP is associated with decreased blood pressure and plasma triglycerides, and reduced risk of coronary artery disease

Linkage of the lipoprotein lipase (LPL) gene to blood pressure levels has been reported. The LPL S447X single nucleotide polymorphism (cSNP) has been associated with decreased triglycerides (TG), increased high density lipoprotein cholesterol, and a decreased risk of coronary artery disease (CAD), which may occur independently of its beneficial lipid changes. To investigate the relationship between LPL S447X cSNP and these parameters, we studied a cohort of individuals with familial hypercholesterolemia in whom blood pressures and information regarding the use of blood pressure lowering medications were available. Carriers of the S447X variant had decreased TG (1.21+/-0.47 vs. 1.52+/-0.67, p<0.001) and a trend towards decreased vascular disease (12.7 vs. 19.5%) compared to non-carriers. More interestingly, however, carriers of this cSNP had decreased diastolic blood pressure compared to non-carriers (78+/-10 vs. 82+/-11, p=0.002), evident in both men and women, youths and adults, with similar trends for systolic blood pressure. Furthermore, the decrease in blood pressure appeared independent of the decrease in TG (p=0.02), suggesting that the LPL protein may have a direct influence on the vascular wall. This suggests an additional mechanism whereby this variant may have protective effects, independent of changes in plasma lipid levels.     

Asthma and atopy are associated with chromosome 17q21 markers in Chinese children

Background:  Single-nucleotide polymorphism (SNP)-based genome-wide association study revealed that markers on chromosome 17q21 were linked to childhood asthma but not atopy in Caucasians, with the strongest signal being detected for the SNP rs7216389 in the ORMDL3 gene. Such association was unknown in Chinese. This study delineated the allele and genotype frequencies of 10 SNPs at chromosome 17q21, and investigated the relationship between these SNPs and asthma and plasma IgE in southern Chinese children.
Methods:  Asthmatic children and non-allergic controls were recruited from pediatric clinics. Their plasma total and aeroallergen-specific IgE concentrations were measured by immunoassay. Ten SNPs on 17q21 region were genotyped by multiplex SNaPshot™, and their genotype associations with asthma traits analyzed using multivariate regression.
Results:  315 patients and 192 controls were enrolled. The allele frequency for C allele of rs7216389 varied significantly from 0.232 in our controls, 0.389 in Han Chinese to 0.536 in Caucasians. Asthma diagnosis was associated with rs11650680 and five other SNPs including rs7216389 ( P  =   0.019–0.034), whereas atopy was associated only with rs11650680 ( P  =   0.0004). Linear regression revealed the covariates for plasma total IgE to be significant for rs11650680 ( P  =   0.008–0.0002). Haplotypic associations were found with atopy and increased plasma total IgE, with the respective odds ratios and 95% confidence intervals for TTTCCGTT haplotype to be 0.21 and 0.09–0.52 ( P  =   0.0002) and 0.41 and 0.18–0.90 ( P  =   0.025).
Conclusion:  Childhood asthma and atopy are associated with chromosome 17q21 in Chinese, but such association may involve genes other than ORMDL3 in this region.     

Increased protein glycation in diabetes mellitus is associated with decreased aspirin-mediated protein acetylation and reduced sensitivity of blood platelets to aspirin

Reduced effectiveness of the most common antiplatelet drug, acetylsalicylic acid (ASA, aspirin), in diabetes mellitus has been associated with a lowered platelet sensitivity to ASA and related to glycemic control in diabetic patients. Our objectives were (a) to monitor the chemical background of how chronic hyperglycemia affects platelet response to ASA in diabetes and (b) to study a chemical competition between the amount of bound acetyl residues and the extent of protein glycation in blood platelets. Using whole-blood impedance aggregometry and platelet function analyzer (PFA-100) we observed a reduced platelet response to ASA in diabetic patients (14% vs. 79% for PFA-100 collagen-epinephrine occlusion time) and an association between the index of glycemic control and platelet refractoriness to ASA (r_S=–0.378). Impaired platelet response to ASA was related to enhanced platelet protein glycation (3.6±0.4 in diabetes vs. 2.3±0.4 µmol fructosamine/µg protein in control) and reduced incorporation of acetyl residue into proteins of platelets from diabetic patients (47.4±2.0 in control vs. 33.1±0.7 µmol acetyl/µg protein in diabetic subjects). Incubation of blood platelets with increasing concentrations of glucose and ASA under in vitro conditions led to excessive modification in protein amino groups: glucose and ASA competed with each other in the course of nonenzymatic modifications, glycosylation, or acetylation, and their contributions to the occupancy of protein amino groups (R²=0.22 for glucose, R²=0.43 for ASA) were dependent upon the concentrations of glucose and ASA. Overall the effects of high glucose and high ASA on the overall occupancy of protein free amino groups are not additive. While at higher concentrations ASA overcomes the effects of hyperglycemia and retards glycation, high glucose makes acetylation less efficient, and therefore the resultant chemical modification becomes greatly reduced. In conclusion, diminished susceptibility of various platelet proteins and receptors on blood platelet membranes to acetylation and high ambient glucose might underlie the apparently differentiated sensitivity of blood platelets to ASA and determine platelet insensitivity to aspirin in diabetic patients     

Active tuberculosis in Africa is associated with reduced Th1 and increased Th2 activity in vivo

Activation of Th1 lymphocytes, IFN-gamma production and macrophage activation are crucial in defense against Mycobacteria. In developing countries, Th2 activation and IL-4 production have been associated in vitro with tuberculosis and with poor clinical outcome after treatment. Serological markers of Th1 [soluble lymphocyte activation gene (LAG)-3] and Th2 (IgE, solubleCD30, and CCL22/macrophage-derived chemokine) activity were measured in 414 HIV-negative tuberculosis patients from The Gambia and Guinée and in 414 healthy household and community controls. Measurements were repeated during treatment to assess the effect of therapy on Th1/Th2 ratio. At diagnosis, sLAG-3 levels were lower in patients than in community controls (p<0.0001), but were higher in household controls exposed to contact with patients than in community controls (p<0.0001). In comparison with community controls, patients had consistently higher levels of IgE, sCD30, and CCL22 (p<0.0001), whereas household controls had lower levels of indicators of Th2 activity (p<0.0001). After treatment, cured patients had higher levels of Th1 (p<0.0001) and lower levels of Th2 (p<0.0001) activity than patients who were not successfully treated or interrupted therapy. In Africa, tuberculosis is associated with low Th1 and high Th2 activity in vivo, whereas close exposure to tuberculosis is associated with a high Th1/Th2 ratio. Patients with favorable outcome after treatment exhibit a higher Th1/Th2 ratio compared to patients with poor clinical outcome.     

Gas,dust, and fumes exposure is associated with mite sensitization and with asthma in mite‐sensitized adults

Occupational exposure to gas, dust, and fumes (GDF) increases the risk of asthma and eczema. We investigated the role of sensitization in the association between GDF and allergic conditions. A population‐based sample of 788 adults from the West Sweden Asthma Study completed questionnaires and skin prick tests. After adjustment for confounders, GDF exposure was associated with a doubled risk of sensitization to mites, but not with other allergens. Mite sensitization also modified the effect of GDF on asthma. In mite‐sensitized subjects, GDF was associated with physician‐diagnosed asthma, adjusted OR 2.9 (1.2–7.2), and with wheeze, OR 2.4 (1.1–5.3). In non‐mite‐sensitized subjects, the corresponding ORs were 1.1 (0.5–2.6) and 0.6 (0.3–1.3). GDF was independently associated with eczema regardless of mite sensitization, but not with rhinitis. These novel findings suggest that components of GDF may act as adjuvants that facilitate sensitization to mites and that mite‐sensitized individuals may be especially susceptible to inhalant occupational exposures.     

Illness Uncertainty, Attributional Style, and Psychological Adjustment in Older Adolescents and Young Adults with Asthma

Examined psychological adjustment in a college sample of olderadolescents and young adults (n=49) with histories of childhoodsthma. A substantial number of subjects evidenced clinicallysignificant levels of overall distress. In addition, greaterperceived asthma uncertainty and increased stable attributionsfor negative events were significantly associated with poorerpsychological adjustment after controlling for demographic anddisease variables. Further analyses revealed a moderating influenceof uncertainty on attribution-adjustment relationships. Thesefindings provide initial support for a cognitive diathesis-stressview of adjustment in long standing asthma. Results also supporta growing body of evidence suggesting that the focus of effortsto enhance adjustment to asthma need to be expanded beyond childhoodand early adolescence.     

Impaired migration of trophoblast cells caused by simvastatin is associated with decreased membrane IGF-I receptor, MMP2 activity and HSP27 expression

BACKGROUND: Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme-A reductase, the rate-limiting enzyme of the mevalonate pathway, and are used successfully in the treatment of hypercholesterolaemia. Statins are contraindicated during pregnancy. Lately, we have shown that simvastatin has adverse affects on human first trimester placental explants' proliferation and migration. The objective of the present study was to investigate the molecules involved in mediating simvastatin's effect on trophoblast cell migration. We hypothesized that simvastatin attenuates insuline-like growth factor-I (IGF-I) receptor expression (involved in trophoblast motility), matrix metalloproteinase (MMP) activities, and heat shock protein 27 (HSP27) levels (whose mRNA is actively transcribed during trophoblast differentiation) in trophoblast cells thus consequently effecting their migration. METHODS: Human placental explants were cultured above a matrigel with/without simvastatin (10 microM) for 5 days. In this model, trophoblast migrates from the villi into the matrigel. Western-blot and immunohistochemistry served for analysing HSP27 expression. Immunohistochemistry was used for assessing IGF-I receptor localization. MMPs activity was assayed by gel zymography. RESULTS: Simvastatin reduced IGF-I receptor membranal expression, MMP2 activity and HSP27 expression in trophoblast cells (P < 0.05). CONCLUSIONS: The inhibitory effect of simvastatin on trophoblast cell migration is associated with a significant decrease in the tested molecules, which probably contributes to the impaired migration.     

Residential exposure to mould and dampness is associated with adverse respiratory health

Background Indoor exposure to mould and dampness is frequently associated with asthma symptoms with and without lung function changes. However, the mechanisms contributing to this threat to respiratory health are only partly understood. Objective To investigate the contribution of recent exposure to mould and dampness in the living room or bedroom to respiratory health in a general practice‐based cohort of 526 asthmatic children. Methods Parents were questioned about home characteristics, including moulds and dampness. The level of asthma control was evaluated in their participating children by means of asthma symptoms, peak expiratory flow (PEF) variability, severity of airway hyperresponsiveness (AHR), and medication usage. Results Children exposed to indoor moulds and dampness more often had severe AHR compared with non‐exposed (42% vs. 16%; P0.001). They also showed an increased PEF variability (11.3% vs. 8.4%; P=0.03) and, however, not significant, more frequent asthma symptoms. The use of controller medication was not significantly different between exposed and non‐exposed children. After adjustment for gender, age, smoking, exposure to parental smoking, parental education, pet ownership, presence of inhalant allergy, use of controller medication, health care center, and season of study assessment, the odds ratio for severe AHR in exposed children was 3.95 [95% confidence interval (CI): 1.82–8.57]. Conclusion We found a consistent association between reported moulds and dampness in the living room or the child's bedroom and an increased risk for severe AHR in a general practice‐based cohort of asthmatic children, even after adjustment for gender, presence of inhalant allergy, and use of controller medication.