Over 1.1 billion people smoke worldwide despite the association of smoking with numerous diseases including chronic obstructive pulmonary disease (COPD). The decline in lung function observed in COPD patients is thought to be related to smoke-induced inflammation. COPD patients are also at increased risk of acquiring lung bacterial infections that are associated with exacerbations, characterized by worsened disease symptoms and inflammation. The focus of this thesis is on how cigarette smoke impacts bacterial-host interactions and bacterial community interactions to promote infection and disease. In chapter 3.1, we sought to understand how cigarette smoke primed the lungs towards an amplified inflammatory response to bacterial infection reflective of COPD exacerbations that accelerate disease progression. We present a novel finding that exacerbated neutrophilia elicited by nontypeable Haemophilus influenzae (NTHi) lung challenge in smoke-exposed mice occurred dependent on IL-1α. Smokers and patients with COPD are additionally at increased risk of acquiring bacterial infection that may be related to impaired containment of nasally colonizing pathogens. In chapter 3.2, we found that cigarette smoke predisposed mice to invasive pneumococcal disease (IPD) following nasal pneumococcal colonization associated with attenuated nasal inflammatory responses. To our knowledge, this is the first study to describe the progression from asymptomatic nasal pneumococcal colonization to the development of IPD in the context of cigarette smoking. It has been suggested that smokers have higher rates of pathogen colonization as a consequence of cigarette smoke-induced nasal microbiome dysbiosis. The last study in chapter 3.3 advanced knowledge in the field by testing this hypothesis. We observed that cigarette smoke alone did not alter the mouse nasal microbiome and concluded that microbiome dysbiosis observed in smokers likely occur as a consequence of nasal pathogen colonization. Overall, work presented in this thesis advanced our understanding of how cigarette smoking alters bacterial-host interactions to promote infection and disease. / Thesis / Doctor of Philosophy (PhD) / Over 1.1 billion people smoke worldwide and can develop chronic obstructive pulmonary disease (COPD), a serious inflammatory disease compromising lung function. Additionally, smokers and COPD patients have higher rates of bacterial infection. The goal of this thesis is to understand how smoking impacts our ability to combat infection. Lung infection in COPD patients causes exacerbation, with worsened disease symptoms. Using mouse models, we learned how smoking causes increased lung inflammation following bacterial infection, contributing to damage reflective of COPD exacerbations, and identified a potential intervention. We elucidated smokers may have increased infections due to impaired immune responses in the nose, a major pathogen entry point. It is thought smoking reduced beneficial bacteria that counter pathogen acquisition in the nose. We confirmed smoking did not impact these bacteria, directing research focus towards other ways smokers acquire pathogens. Overall, this thesis advanced knowledge and will help efforts to control disease in smokers.

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Nous ne sommes plus autorisés à parler de la BPCO comme d'une simple maladie respiratoire mais plutôt comme une maladie générale. Parmi les atteintes systémiques, la dysfonction musculaire apparaît comme un facteur clé dans la physiopathologie de la BPCO car elle domine l'évolution de la maladie. Par ailleurs, le mystère autour de l'origine exacte de cette dysfonction reste encore entier. Il est maintenant bien établi qu'au cours des épisodes d'exacerbations, la dysfonction musculaire atteint son paroxysme, de plus en absence d'accompagnement musculaire spécifique la récupération est quasi nulle. Ainsi, les objectifs de ce travail de thèse ont étés la compréhension des mécanismes impliqués, d'une part, dans la dysfonction musculaire périphérique des patients BPCO stables et instables (après épisode d'exacerbation) et, d'autre part, dans l'amélioration de la fonction musculaire après différents programmes de réentraînements à l'effort. Dans le cadre de notre première étude, nous avons rapporté que l'oxydation des protéines, plus particulièrement les protéines mitochondriales était plus élevée dans le quadriceps des patients avec une BPCO stable. De plus, nous avons montré que les épisodes d'exacerbations sont associés à une augmentation de l'oxydation des protéines, au niveau mitochondriales et contractiles, corrélée à une dysfonction musculaire. Dans un second temps, nous avons envisagé un réentrainement par électrostimulation chez les patients en cours d'exacerbation et un réentrainement individualisé au seuil ventilatoire (intensité modérée) pour les patients cliniquement stables. Nos résultats indiquent que les deux programmes d'entraînement proposés préviennent le stress oxydant musculaire et améliorent la fonction musculaire périphérique chez les patients BPCO. Cependant, les adaptations mitochondriales restent limitées chez les patients BPCO stables comparativement aux sujets contrôles. En conclusion, nos résultats montrent que les protéines contractiles et mitochondriales sont la cible d'une augmentation du stress oxydant musculaire particulièrement au cours d'une exacerbation. Par ailleurs, des programmes de réentraînement adaptés à la sévérité de la fonction musculaire préviennent les dommages liés au stress oxydant musculaire et contribuent à l'amélioration de la fonction musculaire périphérique. Ainsi, nous pensons que nos résultats pourront probablement favoriser l'amélioration de la prescription du réentraînement à l'effort chez les patients BPCO. / We are no longer allowed to consider COPD as a simple respiratory disease but rather as a systemic disease. Among the systemic effects, muscle dysfunction appears to be a key factor in the pathogenesis of COPD because it strongly influences how the disease will progress. However, the exact origin of muscle dysfunction is still unknown. It is acknowledged that during COPD exacerbations muscle dysfunction is worsened and that, in the absence of post-exacerbation muscle training, recovery is slow and partial. Thus, the objectives of this thesis were first to try to understand the cellular mechanisms involved in the peripheral muscle dysfunction in patients with stable and unstable (after exacerbations) COPD and, then, to assess different programs of physical training to improve muscle function in such patients.Concerning the identification of the mechanisms underlying peripheral muscle dysfunction, we found that protein oxidation, particularly mitochondrial protein oxidation, is higher in the quadriceps of patients with stable COPD than in control subjects. In addition, we have shown that COPD exacerbations are associated with increased muscle oxidative damage of mitochondrial and contractile proteins that is correlated with the level of muscle dysfunction. We then assessed a training protocol using neuromuscular electrostimulation for patients during COPD exacerbation and a training program of moderate intensity (ventilatory threshold) for clinically stable patients. Our results indicate that the two training programs prevent oxidative stress and improve muscle function in COPD patients. However, mitochondrial adaptation is limited in patients with stable COPD compared with controls. In conclusion, our results show that contractile and mitochondrial proteins are the target of increased oxidative stress particularly during COPD exacerbation. However, training programs tailored to the severity of muscle dysfunction can prevent further oxidative damage and contribute to improving muscle function. Our findings might help improving the choice of training programs for patients with COPD.

La broncho-pneumopathie chronique obstructive (BPCO) est une maladie inflammatoire chronique des voies aériennes dont le facteur de risque principal est l’exposition chronique à la fumée de cigarette. L’histoire de la maladie est fréquemment associée à une colonisation bactérienne des voies aériennes et ponctuée d’épisodes aigus d’exacerbation de la maladie associés à une morbi-mortalité importante. Ces exacerbations sont principalement d’origine infectieuses et plus particulièrement, associées à une bactérie dans 50 % des cas, majoritairement Haemophilus influenzae, Streptococcus pneumoniae et Moraxella catarrhalis. Le contrôle de ces infections bactériennes implique en particulier une réponse immunitaire de type Th17 efficace. Cette immunité Th17 médiée principalement par les cytokines IL-17A et IL-22 est impliquée dans la physiopathologie de la BPCO mais n’a été que peu étudiée dans le contexte des exacerbations. Notre hypothèse est que la réponse Th17 aux pathogènes est altérée dans la BPCO, mécanisme qui serait impliqué dans la susceptibilité aux infections respiratoires observée chez les patients.Différentes approches ont été utilisées pour tester cette hypothèse. Tout d’abord, une approche ex vivo, à partir de cellules mononucléées circulantes (PBMC) de patients atteints de BPCO comparées à celles issues de sujets sains non fumeurs et de sujets fumeurs sans obstruction bronchique, montrant un défaut de production par les PBMC des cytokines IL-17A et IL-22 mais également des cytokines IL-6 et IL-23 produites par les cellules présentatrices d’antigènes (CPA) et impliquées dans l’activation de cette immunité Th17, en réponse à une activation par S. pneumoniae. Ensuite, une approche in vitro, avec un modèle de cellules dendritiques dérivées de monocytes (MDDC) exposées à la fumée de cigarette. Ces MDDC présentaient un défaut de maturation, de production de cytokines pro-Th17 et de leur capacité à activer une réponse Th17 lymphocytaire en réponse à S. pneumoniae. Enfin, une approche in vivo, utilisant un modèle murin de souris exposées de façon chronique à la fumée de cigarette confirmant ces résultats avec un défaut de réponse IL-17A et IL-22 mais également de production des cytokines pro-Th17 IL-1β et IL-23 par les CPA en réponse à S. pneumoniae. Dans ce modèle, l’apport d’IL-22 permettait d’améliorer la clairance bactérienne et de réduire les lésions pulmonaires, suggérant des possibilités thérapeutiques pour améliorer la prise en charge de ces exacerbations infectieuses.Ces trois approches permettent d’apporter des arguments forts en faveur d’un défaut de réponse Th17 au cours des exacerbations bactériennes de la BPCO, hypothèse confortée par d’autres travaux de notre équipe montrant dans le modèle murin d’exposition chronique à la fumée de cigarette la présence d’un défaut de production d’IL-22 dans la réponse à Haemophilus influenzae. Ces travaux qui doivent maintenant être d’une part, confirmés par une étude clinique incluant des patients atteints de BPCO en exacerbation, et d’autre part, complétés pour préciser l’impact sur les cellules lymphoïdes innées productrices de ces cytokines et sur la réponse de l’épithélium bronchique à l’infection, ouvrent la voies à des perspectives thérapeutiques dans la prise en charge de ces exacerbations bactériennes. / Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the airways mainly due to chronic exposure to cigarette smoke. Evolution of the disease is often associated with bacterial colonization of the airways and punctuated by acute exacerbation of the disease with a frequent related morbi-mortality. These exacerbations are mainly due to infection and almost 50 % are associated with bacteria, often Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis. Th17 immune response is particularly involved in control of bacterial infection and is principally mediated by IL-17A and IL-22 cytokines. This Th17 inflammation is involved in COPD physiopathology but there is paucity of data focusing on this immune response during COPD exacerbations. Our hypothesis is that Th17 immune response to pathogens is defective in COPD leading to airways infection susceptibility.We have tested our hypothesis by different approaches. First, the ex vivo responses to Streptococcus pneumoniae of peripheral blood mononuclear cells (PBMC) from COPD patients, healthy non smokers and healthy smokers were compared showing decreased production of IL-17A and IL-22 but also of pro-Th17 cytokines IL-6 and IL-23 which are produced by antigen presenting cells (APC). Second, we used an in vitro model of monocyte-derived dendritic cells (MDDC) exposed to cigarette smoke showing a defective MDDC maturation, pro-Th17 cytokines production and ability to promote T-cells Th17 response, in response to S. pneumoniae. Finally, an in vivo murine model of mice chronically exposed to cigarette smoke showing defective production of IL-17A and IL-22 but also of pro-Th17 cytokines IL-1β and IL-23 produced by APC, in response to S. pneumoniae. In this model, supplementation with IL-22 restored bacterial clearance and limited lung alterations suggesting therapeutic opportunities to improve infectious COPD exacerbation management.Altogether, these results strengthen our hypothesis of a defective Th17 immune response during bacterial COPD exacerbations. They are comforted by other studies in our team showing a defective IL-22 production in response to Haemophilus influenzae in our in vivo model of mice chronically exposed to cigarette smoke. Now we have to confirm these results in a clinical trial including COPD patients in exacerbation and to further explore the impact on innate lymphoid cells, which produced these cytokines, and on the innate immune response of epithelial cells to infection, in order to develop new infectious COPD exacerbation therapeutics.

Cardiovascular disease is common in Chronic Obstructive Pulmonary Disease (COPD), and forced expiratory volume in one second (FEV1) independently predicts cardiovascular morbidity and mortality. Pathological changes in the systemic vasculature have been proposed as potential mechanisms linking COPD to cardiovascular disease, and patients with COPD may be at increased risk of acute myocardial infarction during acute exacerbations. Notwithstanding causation, FEV1 may be a useful prognostic marker in patients undergoing cardiac surgery. This thesis examined these three aspects of cardiovascular co-morbidity in relation to COPD and FEV1. In 2,241 consecutive cardiac surgery patients, FEV1 was associated with length of hospital stay (p<0.001) and mortality (p<0.001) adjusting for age, sex, height, body mass index, socioeconomic status, smoking, cardiovascular risk factors, chronic pulmonary disease, and type/urgency of surgery. In a survey of Scottish Respiratory Consultants there was no consensus regarding the investigation and management of acute coronary syndrome in exacerbation of COPD. In a case-series of 242 patients with exacerbations 2.5% (95% CI 1.0 to 5.6%) had chest pain, raised serum troponin and serial electrocardiogram changes suggestive of acute coronary syndrome. However, over half reported chest pain, while raised troponin was not associated with chest pain or serial ECG changes. Carotid-radial pulse wave velocity (PWV), aortic distensibility, and aortic calcification were measured to assess the relationship of the systemic vasculature to FEV1 and emphysema severity on CT. In adjusted analyses, emphysema was associated with PWV in patients with COPD (p = 0.006) and, in population based samples, with extent of distal aortic calcification (p=0.02) but not with aortic distensibility (p=0.60). This thesis found that FEV1 was associated with mortality and length of hospital stay in patients undergoing cardiac surgery, and that chest pain and raised troponin were common but unrelated in exacerbation of COPD. In the vascular studies distal but not proximal vascular pathology was associated with FEV1, and if COPD is truly related to systemic arterial disease, the distal arterial tree is implicated.

<p>The aim of this thesis was to investigate health-related quality of life (HRQoL) and coping strategies for individuals with ulcerative colitis (UC) or Crohn’s disease (CD), and to study the effect of a group-based patient information on anxiety/depression and HRQoL. HRQoL and anxiety/depression were investigated (n=492) (Study I). In Study II, anxiety/depression, HRQoL, satisfaction with information and evaluation of the patient information were studied (n=49). Coping with disease activity was investigated in 166 patients reporting current exacerbation (Study III). Fifteen patients were interviewed about disease-related stress, how this is managed and the need of support from the health care (Study IV). Patients with UC reported better HRQoL and less anxiety/depression than did patients with CD during both remission and exacerbation. Satisfaction with information had increased at follow-up 6 months after patient information. The information and the possibility to discuss with lecturers and group members were valued as most important. No change was found in anxiety/depression or HRQoL at follow-up. Both problem-focused and emotion-focused strategies were employed to cope with disease activity, with no difference between patients with UC or CD. The urgent need of toilet availability and stress associated to social situations were the major disease-related stressors. This stress was managed by finding out the location of toilets, bringing toilet paper and extra underwear and emptying bowel before an activity. The patients wanted information and possibilities to talk to experienced staff and to other patients about how to live with the disease. This thesis shows that HRQoL for some patients with UC, and primarily for patients with CD, is impaired. Thus medical staff should be observant of the psychosocial well-being of patients with CD and also of patients with relapse. Methods to identify and support patients with anxiety/depression and poor HRQoL need to be developed. Interventions should target the patient’s specific problems and at appropriate times.</p>

The aim of this thesis was to investigate health-related quality of life (HRQoL) and coping strategies for individuals with ulcerative colitis (UC) or Crohn’s disease (CD), and to study the effect of a group-based patient information on anxiety/depression and HRQoL. HRQoL and anxiety/depression were investigated (n=492) (Study I). In Study II, anxiety/depression, HRQoL, satisfaction with information and evaluation of the patient information were studied (n=49). Coping with disease activity was investigated in 166 patients reporting current exacerbation (Study III). Fifteen patients were interviewed about disease-related stress, how this is managed and the need of support from the health care (Study IV). Patients with UC reported better HRQoL and less anxiety/depression than did patients with CD during both remission and exacerbation. Satisfaction with information had increased at follow-up 6 months after patient information. The information and the possibility to discuss with lecturers and group members were valued as most important. No change was found in anxiety/depression or HRQoL at follow-up. Both problem-focused and emotion-focused strategies were employed to cope with disease activity, with no difference between patients with UC or CD. The urgent need of toilet availability and stress associated to social situations were the major disease-related stressors. This stress was managed by finding out the location of toilets, bringing toilet paper and extra underwear and emptying bowel before an activity. The patients wanted information and possibilities to talk to experienced staff and to other patients about how to live with the disease. This thesis shows that HRQoL for some patients with UC, and primarily for patients with CD, is impaired. Thus medical staff should be observant of the psychosocial well-being of patients with CD and also of patients with relapse. Methods to identify and support patients with anxiety/depression and poor HRQoL need to be developed. Interventions should target the patient’s specific problems and at appropriate times.

Asthma is a chronic respiratory disease characterized by inflammation of the airway and the presence of recurrent attacks (exacerbations) of breathlessness, wheezing, cough, chest tightness, or some combination of these symptoms. In the US, about 53% of people with asthma had an asthma attack in 2008, and 57% of these, were children. One in ten children (10%) had asthma in 2009, and boys were more likely than girls to have asthma. Internationally, the prevalence of asthma varies widely in different countries, but the disparity is narrowing due to rising prevalence in low and middle income countries. Unfortunately, we do not have statistics for asthma in the Republic of Panama, neither epidemiological data nor costs, which is the reason why this research is needed. The Panamanian Social Security Fund (CSS) provides protection to workers, their immediate families and the pensioned. By the end of 2010, the total insured population was 2,862,202 (83% of the total population of Panama). Of the total insured population 58% were dependent. Of this, 1,205,607 (42%) were children. On the basis of this information, we decided to develop the research study using information from the CSS, specifically in the Hospital de Especialidades Pediatricas (HEPOTH). It is the only tertiary level of healthcare children's hospital of the CSS. A quantitative-descriptive design was used to develop this study. Data was collected from medical records of patients diagnosed with asthma in the HEPOTH from January to June 2012. We reviewed the medical records of each care area by month, and numbered each clinical record of children diagnosed with asthma in crisis and randomly selected 10% of the medical records from a minimum of 2000 records. Information on treatment costs was also obtained. Once all the information was collected, it was typed in the digital data log created for this study and the responses were code converted and the information was entered into a database. The data were exported to IBM SPSS Statistics 21. The average cost of asthma attacks in Panama is estimated at $205.52. We were able to confirm that there are variations in this average by gender, age, geographic area of residence, season, severity, whether treated in the emergency department or hospitalization, and the type of treatment received. It was also possible to obtain secondary information about the epidemiology of asthma that allowed us to confirm that our statistics matched international statistics.

Lėtinė obstrukcinė plaučių liga pasireiškia nevisiškai išnykstančia kvėpavimo takų obstrukcija, kuri įprastai progresuoja ir sutrikdo kvėpavimo takų pralaidumą bei dujų apykaitą plaučiuose ir audiniuose. Pasaulinės sveikatos organizacijos (PSO) duomenimis lėtine obstrukcine plaučių liga serga apie 600 mln. žmonių. Lietuvoje statistikos duomenimis 2012 metais sirgo apie 60 tūkstančių žmonių. Šie skaičiai verčia jieškoti lėtinės obstrukcinės plaučių ligos problemų sprendimo būdų. Vienas iš tokių būdų yra plaučių ligomis sergančiųjų reabilitacija. Moksliniais tyrimais įrodyta, kad efektyviausia reabilitacija yra tuomet , kai ji pradedama iš karto po ligos paūmėjimo. Garsų mankšta mažina bronchų reaktyvumą ir bronchospazmą, aktyvūs kvėpavimo pratimai stiprina kvėpavimo raumenis, gerina atsikosėjimą, stiprina kvėpavimo raumenis bei skatina širdies ir kraujagyslių veiklą, o tuo pačiu ir plaučių kraujotaką. Tyrimo tikslas : Įvertinti skirtingų kineziterapijos metodų efektyvumą gydant sergančiuosius lėtine obstrukcine plaučių liga ūmiu ligos laikotarpiu. Uždaviniai : 1. Išanalizuoti tiriamųjų rizikos veiksnius, būdingus lėtinei obstrukcinei plaučių ligai. 2. Įvertinti tiriamųjų dusulio laipsnį. 3. Nustatyti tiriamųjų plaučių ventiliacijos rodiklius, kraujo spaudimo bei krūtinės ląstos ekskursiją prieš ir po kineziterapijos. 4. Palyginti tiriamųjų, kuriems buvo taikyta garsų mankšta ir tiriamųjų, kuriems buvo taikyti aktyvūs kvėpavimo pratimai, visus... [toliau žr. visą tekstą] / The chronic obstructive lung disease is characterized by presence of airways obstruction which, as a rule, would be progressing and disturbing airflow passing and gas exchange in lungs and tissues. According to the World Health Organisation (WHO) data approximately 600 million people suffer from chronic obstructive lung disease. The Lithuanian statistic data show that in 2012 about 60 thousand Lithuanian residents had this disease. The above figures make us look for solutions to the problems created by chronic obstructive lung disease. One of the ways is rehabilitation of patients with lung diseases. The scientific research proved that the rehabilitation was most efficient when commenced immediately following exacerbation of the disease. Speech-language exercises reduce bronchi reactivity and bronchospasm, active breathing exercises strengthen the breathing muscles, improve expectoration, strengthen breathing muscles and stimulate better heart and blood vessels performance at the same time resulting in better blood circulation in lungs. Goal of the study: to assess the effectiveness of different physiotherapy methods in treatment of chronic obstructive lung disease in the acute stage. Objectives: 1. to analyse the risk factors in patients under study typical of the chronic obstructive lung disease; 2. to evaluate the degree of dyspnoea in patients under study; 3. to establish lung ventilation, blood pressure and thorax excursion values in patients... [to full text]

Lėtinė obstrukcinė plaučių liga (LOPL) – šiuo metu pasaulyje viena svarbiausių didelį sergamumą ir mirtingumą sąlygojančių ligų. Pacientams, kuriems pasunkėja kasdieniai LOPL simptomai pasireiškia LOPL paūmėjimas. Šio tyrimo tikslas – įvertinti nespecifinį uždegimą paūmėjus lėtinei obstruk¬cinei plaučių ligai. Nustatyti periferinio kraujo ir indukuotų skreplių ląstelių sudėties skirtumai ir įvertintos sąsajos su plaučių funkcijos rodikliais bakterinio ir nebakterinio lėtinės obstrukcinės plaučių ligos paūmėji¬mo metu. Tirtos sergančiųjų bakterinės kilmės lėtinės obstrukcinės plaučių li¬gos paūmėjimo indukuotų skreplių neutrofilų ir makrofagų funkcijos (apoptozė, fagocitozė ir reaktyvių deguonies formų susidarymas) bei palygintos su nebakteriniu paūmėjimu. Įvertinti sergančiųjų bakterinės ir nebakterinės kilmės lėtinės obs¬trukcinės plaučių ligos paūmėjimo periferinio kraujo neutrofilų ir monocitų apoptozė ir chemotaksis, bei periferinio kraujo neutrofilų fagocitozė ir reaktyvių deguonies formų susidarymas. Ištirta sergančiųjų bakterinės ir nebakterinės kilmės lėtinės obstruk¬cinės plaučių ligos paūmėjimu interleukino-8 koncentracija ir sąsajos su periferinio kraujo neutrofilų chemotaksiu bei C reaktyviojo baltymo koncentracijos periferinio kraujo serume sąsajos su plaučių funkcija ir rūkymo intensyvumu. / Chronic obstructive pulmonary disease (COPD) – a common preventable and treatable disease, is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. An acute exacerbation of COPD (AECOPD) is an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication. The aim of this study was to evaluate the non-specific inflammation during acute exacerbation of COPD to investigate change of cellular activity (apoptosis, chemotaxis, phagocytosis and production of reactive oxygen species) during AECOPD depending on infection agent. Subjects with AECOPD and the same in remission were investigated. Increased count of induced sputum neutrophils and macrophages as well peripheral blood neutrophils and monocytes during bacterial and non-bacterial AECOPD was related with impaired pulmonary function and smoking history. Induced sputum neutrophils and macrophage apoptosis and phagocytosis were weaker, but production of reactive oxygen species was strongly activated during bacterial acute exacerbation of chronic obstructive pulmonary disease than non-bacterial AECOPD. This study showed differences of peripheral blood neutrophil and monocyte apoptosis, chemotaxis, as well as peripheral blood neutrophil phagocytosis and the production of reactive oxygen species... [to full text]