Genes Involved in Systemic and Arterial Bed Dependent Atherosclerosis - Tampere Vascular Study

BACKGROUND: Atherosclerosis is a complex disease with hundreds of genes influencing its progression. In addition, the phenotype of the disease varies significantly depending on the arterial bed. METHODOLOGY/PRINCIPAL FINDINGS: We characterized the genes generally involved in human advanced atherosclerotic (AHA type V-VI) plaques in carotid and femoral arteries as well as aortas from 24 subjects of Tampere Vascular study and compared the results to non-atherosclerotic internal thoracic arteries (n=6) using genome-wide expression array and QRT-PCR. In addition we determined genes that were typical for each arterial plaque studied. To gain a comprehensive insight into the pathologic processes in the plaques we also analyzed pathways and gene sets dysregulated in this disease using gene set enrichment analysis (GSEA). According to the selection criteria used (>3.0 fold change and p-value <0.05), 235 genes were up-regulated and 68 genes down-regulated in the carotid plaques, 242 genes up-regulated and 116 down-regulated in the femoral plaques and 256 genes up-regulated and 49 genes down-regulated in the aortic plaques. Nine genes were found to be specifically induced predominantly in aortic plaques, e.g., lactoferrin, and three genes in femoral plaques, e.g., chondroadherin, whereas no gene was found to be specific for carotid plaques. In pathway analysis, a total of 28 pathways or gene sets were found to be significantly dysregulated in atherosclerotic plaques (false discovery rate [FDR] <0.25). CONCLUSIONS: This study describes comprehensively the gene expression changes that generally prevail in human atherosclerotic plaques. In addition, site specific genes induced only in femoral or aortic plaques were found, reflecting that atherosclerotic process has unique features in different vascular beds

Striatal Patchwork of D1-like and D2-like Receptors Binding Densities in Rats with Genetic Audiogenic and Absence Epilepsies

Binding densities to dopamine D1-like and D2-like receptors (D1DR and D2DR) were studied in brain regions of animals with genetic generalized audiogenic (AGS) and/or absence (AbS) epilepsy (KM, WAG/Rij-AGS, and WAG/Rij rats, respectively) as compared to non-epileptic Wistar (WS) rats. Convulsive epilepsy (AGS) exerted a major effect on the striatal subregional binding densities for D1DR and D2DR. An increased binding density to D1DR was found in the dorsal striatal subregions of AGS-prone rats. Similar changes were seen for D2DR in the central and dorsal striatal territories. Subregions of the nucleus accumbens demonstrated consistent subregional decreases in the binding densities of D1DR and D2DR in epileptic animals, irrespective of epilepsy types. This was seen for D1DR in the dorsal core, dorsal, and ventrolateral shell; and for D2DR in the dorsal, dorsolateral, and ventrolateral shell. An increased density of D2DR was found in the motor cortex of AGS-prone rats. An AGS-related increase in binding densities to D1DR and D2DR in the dorsal striatum and motor cortex, areas responsible for motor activity, possibly reflects the activation of brain anticonvulsive loops. General epilepsy-related decreases in binding densities to D1DR and D2DR in the accumbal subregions might contribute to behavioral comorbidities of epilepsy

Striatal Patchwork of D1-like and D2-like Receptors Binding Densities in Rats with Genetic Audiogenic and Absence Epilepsies

Binding densities to dopamine D1-like and D2-like receptors (D1DR and D2DR) were studied in brain regions of animals with genetic generalized audiogenic (AGS) and/or absence (AbS) epilepsy (KM, WAG/Rij-AGS, and WAG/Rij rats, respectively) as compared to non-epileptic Wistar (WS) rats. Convulsive epilepsy (AGS) exerted a major effect on the striatal subregional binding densities for D1DR and D2DR. An increased binding density to D1DR was found in the dorsal striatal subregions of AGS-prone rats. Similar changes were seen for D2DR in the central and dorsal striatal territories. Subregions of the nucleus accumbens demonstrated consistent subregional decreases in the binding densities of D1DR and D2DR in epileptic animals, irrespective of epilepsy types. This was seen for D1DR in the dorsal core, dorsal, and ventrolateral shell; and for D2DR in the dorsal, dorsolateral, and ventrolateral shell. An increased density of D2DR was found in the motor cortex of AGS-prone rats. An AGS-related increase in binding densities to D1DR and D2DR in the dorsal striatum and motor cortex, areas responsible for motor activity, possibly reflects the activation of brain anticonvulsive loops. General epilepsy-related decreases in binding densities to D1DR and D2DR in the accumbal subregions might contribute to behavioral comorbidities of epilepsy

Daily physical activity and lung function decline in adult-onset asthma:a 12-year follow-up study

Abstract Background: There is a lack of knowledge on the association between daily physical activity and lung function in patients with asthma. Objective: This study aims to examine the association between daily physical activity and asthma control, lung function, and lung function decline in patients with adult-onset asthma. Design: This study is part of Seinäjoki Adult Asthma Study (SAAS), where 201 patients were followed for 12 years after asthma diagnosis. Daily physical activity was assessed at follow-up by a structured questionnaire and used to classify the population into subgroups of low (≤240 min) or high (>240 min) physical activity. Three spirometry evaluation points were used: 1. diagnosis, 2. the maximum lung function during the first 2.5 years after diagnosis (Max0–2.5), 3. follow-up at 12 years. Results: High physical activity group had slower annual FEV1 (p&lt;0.001) and FVC (p&lt;0.018) decline. Additionally, the high physical activity group had higher FEV₁ values at follow-up, and higher FEV₁/FVC ratios at follow-up and diagnosis. There was no difference in BMI, smoking, medication, or frequency of physical exercise between high and low physical activity groups. Differences remained significant after adjustments for possible confounding factors. Conclusion: This is the first demonstration of an association between long-term FEV₁ decline and daily physical activity in clinical asthma. Low physical activity is independently associated with faster decline in lung function. Daily physical activity should be recommended in treatment guidelines in asthma

12-year adherence to inhaled corticosteroids in adult-onset asthma

Abstract Adherence to inhaled corticosteroids (ICS) has been suggested to be poor but long-term follow-ups are lacking. The objective of the present study was to assess adherence to ICS treatment in patients with adult-onset asthma during 12-year follow-up. A total of 181 patients with clinically confirmed, new-onset adult asthma were followed for 12 years as part of the Seinäjoki Adult Asthma Study. Adherence to ICS was assessed individually as the percentage of true dispensed ICS in micrograms per true prescribed daily ICS in micrograms over 12 years. Mean 12-year adherence to ICS was 69% (mean±sd dispensed 2.5±1.8 g and prescribed 3.6±1.5 g budesonide equivalent per patient for 12 years), annual adherence varying between 81% (year 1) and 67% (year 12). Patients with good 12-year adherence (≥80%) used oral corticosteroids more often, and had add-on drugs in use and asthma-related visits to healthcare more often. In addition, they showed less reversibility in forced expiratory volume in 1 s and had higher peripheral blood neutrophil counts. However, lung function decline was steeper in patients with poorer adherence (&lt;80%) and this association remained in multiple linear regression analysis. No difference was found in symptom scores, blood eosinophil counts, exhaled nitric oxide or immunoglobulin E between the patients with different levels of adherence. In patients with adult-onset asthma, adherence to ICS was moderate. Poorer adherence (&lt;80%) to ICS was associated with more rapid decline in lung function but was not associated to symptoms or markers of inflammatory endotypes

Association between blood eosinophils and neutrophils with clinical features in adult-onset asthma

Abstract Background: Asthma is a disease that can be separated into different phenotypes and endotypes based on the clinical characteristics and the molecular mechanisms of the condition, respectively. Objektive: To assess the association between blood eosinophil and neutrophil counts with clinical and molecular features in patients with adult-onset asthma. Methods: Blood eosinophil and neutrophil counts were measured from 203 patients who took part in the Seinäjoki Adult Asthma Study and attended the 12-year follow-up visit. The patients were then divided into four groups (paucigranulocytic [n = 108], neutrophilic [n = 60], eosinophilic [n = 21], and mixed granulocytic [n = 14]), according to eosinophil and neutrophil levels. The cutoff values used to define the groups were 0.30 × 109 · L-1 for blood eosinophils and 4.4 × 109 · L-1 for blood neutrophils. Results: The neutrophilic group had highest body mass index. It was dispensed the highest doses of inhaled corticosteroids during the 12-year follow-up and made the most unplanned respiratory visits. The neutrophilic, eosinophilic, and mixed granulocytic groups had more severe asthma compared with the paucigranulocytic group. The neutrophilic and eosinophilic groups were associated with higher dispensed antibiotics. The eosinophilic group had more nasal polyps, more suspected sinusitis, a greater decline in lung function, and increased levels of periostin, FeNO, and IgE. The neutrophilic group had increased high-sensitivity C-reactive protein, matrix metalloproteinase-9, IL-6, leptin, and soluble urokinase plasminogen activator receptor levels. The mixed granulocytic group showed increased resistin levels together with the neutrophilic group. Conclusions: In addition to blood eosinophils, the blood neutrophil count reflects underlying inflammatory patterns and indicates important differences in asthma clinical features and outcomes