Abstract Although smoking in adolescents and young adults has been declining in the 21st century in Finland, about 17% of 18-year-olds still smoke on a daily basis. Young adults are in fact one of the age groups that are most likely to smoke in several countries. Nevertheless, a large proportion of them are known to want to quit smoking. Relatively little is known about the smoking habits of young adults. There are no evidence-based guidelines for smoking cessation in this age group. In many cases, they have been included within studies of adolescents or older adults without any separate analysis. Consequently, smoking cessation interventions demonstrated to be effective in middle-aged smokers are often adapted for young adults even though their culture, somatic features and smoking habits in many ways are different from those of middle-aged people. This study focused on 18–26-year-olds in northern parts of Finland. Specific aims were 1) to describe their smoking habits, 2) to compare health and lifestyle in tobacco users and non-tobacco users, 3) to study their nicotine dependence and motivation to quit smoking, and 4) to examine the use and effectiveness of smoking cessation pharmacotherapy in this age group. A total of 1163 male military recruits from northern parts of Finland filled in the study questionnaire. The survey study revealed that young adult males in northern parts of the country used tobacco products relatively often. Their smoking was associated with lower education, higher body mass index, inactivity in sports and impaired physical fitness. In addition, a great part of young smokers displayed symptoms of chronic bronchitis. Although most daily smokers were clearly dependent on nicotine and had previously tried to quit smoking, only 47% of the quitters had utilized any pharmacological aids in their attempts. Snus use seemed to be related to more severe nicotine dependence in smokers. The prospective study consisted of 314 voluntary young adult daily smokers who were motivated to quit smoking. The study was a randomised, placebo-controlled clinical trial, and the results indicated that varenicline might be more effective than nicotine patches in smoking cessation of young adult heavy smokers, at least in short term. Abstinence rates during the follow-up were similar when the nicotine patch and placebo patch were compared in young adult light smokers. / Tiivistelmä Suomessa nuorten keskuudessa tupakointi on ollut 2000-luvun aikana laskusuuntainen. Kuitenkin arviolta n. 17 % 18-vuotiaista tupakoi edelleen päivittäin. Nuoret aikuiset ovatkin useissa maissa yksi eniten tupakoivia ikäryhmiä. Silti suuren osan tupakoivista nuorista aikuisista on todettu olevan halukkaita llopettamaan tupakoinnin. Nuorten aikuisten tupakointia on tutkittu verrattain vähän. Heille suunnattuja tieteelliseen näyttöön perustuvia hoitomuotoja tupakoinnin lopettamiseen ei ole. He ovat usein osana teini-ikäisten tai vaihtoehtoisesti vanhempien aikuisten ryhmää tupakointiin liittyvissä tutkimuksissa, eikä heitä yleensä ole analysoitu erikseen. Usein heitä hoidetaankin keski-ikäisiltä aikuisilta saadun tutkimusnäytön pohjalta. Kuitenkin nuorten kulttuuri, biologinen pohja ja tupakointitavat eroavat merkittävästi vanhemmista tupakoitsijoista. Tämä työ on keskittynyt tutkimaan 18–26-vuotiaita nuoria aikuisia Pohjois-Suomessa. Sen tavoitteina on ollut 1) kuvata heidän tupakointitottumuksiaan, 2) selvittää tupakoinnin yhteyttä terveyteen ja elämäntapaan, 3) tutkia heidän nikotiiniriippuvuuttaan sekä motivaatiota lopettaa tupakointi, sekä 4) selvittää tupakkavieroituslääkkeiden käyttöä ja niiden tehoa tässä ikäryhmässä. Terveystottumuskyselyymme vastasi 1163 Pohjois-Suomen varusmiestä. Selvisi, että varusmiehet käyttivät tupakkatuotteita Pohjois-Suomessa valtakunnallisia arvioita enemmän. Tupakoinnin todettiin liittyvän varusmiehillä alempaan koulutustasoon, suurentuneeseen painoindeksiin, vähäisempään fyysiseen aktiivisuuteen ja huonompaan aerobiseen suorituskykyyn. Lisäksi tupakoivilla varusmiehillä kroonisen bronkiitin oireet olivat yleisiä. Vaikka valtaosa heistä oli selvästi nikotiiniriippuvaisia ja oli yrittänyt lopettaa tupakointinsa, vain 47% lopetusta yrittäneistä oli kokeillut tupakkavieroituslääkettä. Nuuskan käyttö vaikutti liittyvän vahvempaan nikotiiniriippuvuuteen tupakoitsijoilla. Prospektiiviseen, satunnaistettuun ja lumekontrolloituun kliiniseen kokeeseen osallistui 314 vapaaehtoista päivittäin tupakoivaa nuorta aikuista, jotka olivat halukkaita tupakoinnin lopetukseen. Tulokset viittasivat siihen, että varenikliini saattaa olla nikotiinilaastaria tehokkaampi tupakoinnista vieroituksessa vahvasti nikotiiniriippuvaisilla nuorilla aikuisilla ainakin lyhyellä aikavälillä. Kevyemmin tupakasta riippuvaisilla nikotiinilaastari ei ollut lumelaastaria tehokkaampi.

INTRODUCTION: The percentage of seniors in the population is increasing worldwide and Europe is not an exception in this case. Geriatric patients create a very specific group of patients in which the risk of drug-related problems is increased due to many reasons. Explicit criteria of potentially inappropriate medications/drug procedures (PIMs) in the aged belong to instruments helping with the evaluation of the quality of drug prescribing to older patients and have been developed in the past decades with the aim to increase the quality of geriatric pharmacotherapy and to minimize the quantity and severity of adverse drug reactions. The aim of this thesis is to evaluate the registration rates and OTC availability of pharmaceuticals from the PIMs list created for the purposes of EU COST Action IS1402 initiative (2015-2018) in 5 countries - Czech Republic, Estonia, Croatia, Poland and Slovakia. METHODOLOGY: Based on the thesis by S. Grešáková, MS, a list of 487 potentially inappropriate medicines/drug procedures in the aged has been created and subsequently also the record table stating the individual PIMs and other requested characteristics that was later filled by research teams of participating countries in the period from December 2016 to April 2017. In each country the following attributes were monitored:...

INTRODUCTION: The issue of care for older patients has recently been discussed more and more frequently. The proportion of older adults in the population has been raising exponentially, especially in the last few decades, so the expectations concerning the extent and quality of geriatric care increases as well. In order to improve the quality of pharmacotherapy in the old age, many tools have been published in the last 25 years aimed at support of physicians in better care for older adults, enabling selection of safer pharmacotherapeutic startegies that respect specific pharmacological, physiological and homeostatic changes in the old age. Consequently, multiple explicit criteria of potentially inappropriate drugs and drug procedures (PIMs) have been published to help clinicians to distinguish pharmacotherapeutic strategies of choice for geriatric patients and oppositely to identify drugs, indications and dosing schedules potentially inappropriate in seniors. The aim of this diploma thesis was to evaluate in the pilot round the registration rates and other issues related to availability of all known PIMs in countries participating in the EU COST Action IS1402 study. METHODOLOGY: Based on diploma thesis of S. Grešáková, MS ("Application of explicite criteria of medications potentially inappropriate...

Introduction: Proportion of the population over the age of 65 is continuously increasing in the European Union, and therefore, the number of polymorbid patients with polypharmacy, limited functional capacities and syndrome of geriatric frailty is rising every year as well. In order to support the quality of geriatric prescribing and to lower possible adverse drug events, explicit criteria for potentially inappropriate drugs and drug procedures for elderly have been created. The aim of the diploma thesis was to evaluate how many potentially inappropriate medications (PIMs) for elderly out of 22 explicit criteria were registered in 6 countries (Czech Republic, Hungary, Portugal, Serbia, Spain and Turkey) participating at the 1st phase of the EU COST Action IS1402 initiative and which criterion or what group of regional criteria (European, American, Asian) would be the most specific and most suitable in individual countries for prospective international study following the quality of PIM prescribing. Methods: Of 22 explicit criteria of drugs/drug procedures potentially inappropriate in the old age, validated and published in peer-review journals and journals with the impact factor by 2015 year, a list of all until now known 345 PIMs was created (disregarding the dosage scheme, interval of use or...

La trisomie 21 est la première cause de retard mental, phénotype majeur de la maladie. Elle est due à la présence d’un chromosome 21 supplémentaire. De nombreux gènes sont présents sur ce chromosome mais quelques-uns ont été proposés comme candidats pour les phénotypes neurocognitifs associés à la maladie, notamment le gène Dyrk1a. Il code pour une sérine-thréonine kinase, DYRK1A, à rôle majeur dans le développement cérébral et l’activité synaptique. Le cortex préfrontal sous-tend un ensemble de fonctions cognitives supérieures dont les fonctions exécutives et est impliqué dans la régulation du comportement émotionnel et de l’humeur, composantes largement affectées dans la trisomie 21. Ce travail de thèse a permis de caractériser des défauts majeurs de la transmission et la plasticité synaptique glutamatergique au sein du cortex préfrontal de deux modèles murins différents de trisomie 21: le modèle mBACtgDyrk1a surexprimant le gène murin Dyrk1a et le modèle Ts65Dn surexprimant 130 gènes de l’analogue murin du chromosome 21 dont Dyrk1a. Un autre versant de l’étude a concerné l’utilisation d’un composé inhibiteur de l’activité DYRK1A ou d’autres cibles cellulaires pour corriger les altérations préfrontales observées, constituant ainsi de nouvelles pistes thérapeutiques pour les phénotypes neurocognitifs associés à la trisomie 21. / Down syndrome is the major cause of mental retardation, the main phenotype of the pathology. It is due to an extra chromosome 21. Many genes have been proposed as candidates for the neurocognitive phenotypes of Down syndrome, notably Dyrk1a. It encodes the serine-threonine kinase DYRK1A which is involved in brain development and synaptic functions. The prefrontal cortex mediates higher cognitive functions, such as executive functions and emotional regulation. This study highlighted major deficits in prefrontal cortex glutamatergic transmission and plasticity of two mouse models for Down syndrome: the overexpressing Dyrk1a mBACtgDyrk1a model and the Ts65Dn model, overexpressing around 130 murine orthologous genes of HSAS21 chromosome. Another aspect of this study was the development of new effective therapeutic strategy for Down syndrome neurocognitive phenotypes based on DYRK1A or other cellular targets activity inhibition.

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In Europa leiden etwa 120 Millionen aller 18- bis 80-jährigen an einer Hörbehinderung (16% Prävalenz). Die altersassoziierte Innenohrschwerhörigkeit (Age related hearing impairment, ARHI) hat damit Anschluss gefunden an die großen Volkskrankheiten: Ischämische Herzerkrankungen (5,9 %), Demenz (5,8 %), Diabetes mellitus und Cerebralen Erkrankungen (je 5,5 %). Der erste Teil der Arbeit befasst sich mit der Theorie des Hörens und seinen Störungen, der cochleären Durchblutung, den metabolischen Risikofaktoren, der Molekularbiologie und Epigenetik des Innenohres. Obwohl in der Literatur weitgehend Konsens über den Einfluss exogener Faktoren auf ARHI herrscht, wie Diabetes mellitus, Herz-Kreislauferkrankungen (Framingham Studie und CVD), Hypertonie, Rauchen, Body mass index (BMI) und genderspezifische hormonelle Einflüsse, gibt es kaum HNO-ärztliche Studien dazu. Der zweite Teil geht in einer Praxis-Fallstudie an 202 Patienten folgenden Fragen nach: 1. Gibt es zwischen metabolischen Erkrankungen, wie Adipositas, Störungen des Fett- und Glucosestoffwechsels, der Hypertonie und der Zunahme von Innenohrschwerhörigkeiten im Erwachsenenalter klinische Zusammenhänge? 2. Könnte eine erste Ohrsymptomatik Prädikator einer okkulten pathologischen Stoffwechselveränderung sein? 3. Gibt es Möglichkeiten einer Prävention? Im Ergebnis zeigten sich bei Patienten mit ARHI im Verhältnis Männer/Frauen: Störung des Glukosestoffwechsels bei 97 %/84 %, Lipidstoffwechselstörungen bei 76 %/85 %, eine Homocysteinämien bei 70 %/62 %, ein Anstieg des Plasminogen-Aktivator-Inhibitors (PAI) bei 65 %/38 % und eine Harnsäureerhöhung bei 48 %/15 %. Auch bei ersten Ohrsymptomen (Ohrdruck, Tinnitus, einzelne Frequenzsenken) fanden sich in jedem einzelnen Fall metabolische Veränderungen, die entweder allein oder in unterschiedlichen Kombinationen vorlagen. Männern mit metabolisch initiierten KHK-Erkrankung haben als Prädikator häufig eine erektile Dysfunktion. Erste auditorische Symptomen könnten Prädikator okkulter metabolischer Störungen bei Männern und Frauen sein. Anamnestisch unklare Innenohrprobleme sollten daher auf Stoffwechselstörungen untersucht werden, da diese Risikofaktoren darstellen, die leitlinienbasiert zu therapieren sind. Eine Prognose ist in keinem Einzelfall möglich, da die Folgen auf die molekularbiologischen Prozesse im Innenohres individuell nicht erkennbar sind. Doch sahen wir bei einigen Patienten deutliche Verbesserungen der Symptome und einen Hörschwellenanstieg. Andere Patienten zeigten innerhalb des Beobachtungszeitraums keine Änderung der audiogenen Symptomatik. Behandlungen über einen längeren Zeitraum an einer größeren Fallzahl wären daher sinnvoll. Die Ergebnisse könnten als erste sekundärpräventive Behandlung betrachtet werden, die im Einzelfall eine Hörgeräteversorgung entbehrlich machte. Sie stellen einen Beitrag zu Pfisters Empfehlung dar, mit den vorhandenen Erkenntnissen exogener Risikomechanismen, dringend neue therapeutische Präventionsstrategien für die HNO-ärztliche Tätigkeit zu entwickeln, die die neurale und molekulare Basis anstelle der Symptome der Erkrankung fokussieren.

55 Abstract Frequency of selected genetic polymorphisms of cytochrome P450 in the Czech population and the influence of CYP2C9 genotype on the hypolipidemic effect of fluvastatin Introduction: One of the main factors of genetically determined variability in response of humans to administered drugs are differences in catalytic activity of metabolizing enzymes, which are caused mainly by genetic polymorphisms in cytochrom P450 family enzymes. This thesis consists of two parts and it is presented as a commentary to the original papers. The first aim was to investigate the frequency of functionally important variant alleles of three main isoenzymes of cytochrome P450 gene: CYP2D6, CYP2C9, CYP2C19, throughout the Czech population, predict the prevalence of poor metabolizer phenotypes, and then to compare the results to the data from other populations. Secondly, we analysed the correlation between the CYP2C9 genotype and cholesterol-lowering effect of fluvastatin in human hypercholesterolemic patients. Methods: Genotypes were determined by PCR-RFLP. The presence of alleles CYP2D6*1, *6, *5, *4, *3, and gene duplication was analysed in 233 healthy volunteers, CYP2C9*1, *2 and*3 in 254 subjects and CYP2C19*1, *2 and *2 in 218 subjects. Eighty seven patients on fluvastatin therapy, and 48 patients on monotherapy...

Objective: This study aims to ascertain once and for all whether children and adolescents affected by ADHD show a higher risk for accidents, as well as investigating a possible association between the administration of ADHD-specific medication and the occurrence of accidents. Method: Two exceptionally large sets of data were implemented in this analysis. Participants included children and adolescents representative of the entire German population. Data for Survey 1 was collected through extensive administration of questionnaires. Data for Survey 2 stemmed from the records of a leading German health insurance company. In terms of statistical analysis, chi-square tests as well as logistic regression analyses were applied and odds ratios (ORs) were determined. Results: Innovative results are presented showing a significantly higher likelihood for ADHD-affected youngsters to be involved in accidents compared with their nonaffected counterparts (Survey 1: OR = 1.60; Survey 2: OR = 1.89) but lacking an overall significant influence of medication regarding the occurrence of accidents (Survey 1: OR = 1.28; Survey 2: OR = 0.97). Frequency of accidents could be predicted by ADHD, gender, and age in both samples. Medication intake served as a weak predictor only in Survey 2. Conclusion: It has been determined in two representative and independent German samples that youngsters with ADHD are at a significantly higher risk of being involved in accidents. In the future, this should always be considered when setting up a treatment plan to ensure a safer and healthier coming of age without relying solely on specific effects of medication.

Primary sclerosing cholangitis (PSC) is a rare chronic liver disease characterized by inflammation and fibrosis of the biliary ducts, resulting in cholestasis and eventually liver failure. No effective treatment is currently available and most patients ultimately require liver transplantation in order to survive. The underlying mechanisms of the disease is poorly understood but a range of hypotheses exist, many of which recognize and grapple with PSC's close relationship with inflammatory bowel disease. Most agree genetics is involved, predisposing for an imbalance in 1) bile acid metabolism, 2) immune response and/or 3) gut microbiota. This literature study aims to describe and elucidate recent progress in the field of pharmacotherapy, as it relates to PSC and our current understanding of the disease. Covered in this study is a total of seven randomized, controlled trials, published between 2015-2022, and available through the medical database/search engine PubMed. Endpoints of particular note are ALP and ELF. ALP, or alkaline phosphatase, is an enzyme found in the liver. Rising levels of ALP in the blood stream is indicative of liver damage. ELF, or Enhanced Liver Fibrosis, is a blood test measuring markers of fibrosis, useful in assessing and staging fibrosis in chronic liver disease. Drugs included in this literature study are aldafermin, cilofexor, fenofibrate, norUrsodeoxicholic acid, obeticholic acid, simtuzumab and vancomycin. With the exception of aldafermin and simtuzumab, all showed promise as ALP reducing agents, in general lowering levels with 15-40 percent. In the case of fenofibrate, a reduction of 65 percent was observed. Of the drugs measured against ELF, only aldafermin produced a statistically significant reduction in fibrosis markers. At the time being it is not entirely clear what to make of the results, due to uncertainties surrounding ALP as a prognostic marker. To what extent ALP predicts transplantation free survival is still a matter of debate. Although considerable efforts have been made to further our understanding of PSC, much is yet to be solved. With regards to pharmacotherapy, the field is experiencing somewhat of a renaissance, showcased by the dozen on-going randomized, controlled trials on a plethora of potential PSC substances. Thus, the search for an effective therapy against PSC goes on.