Les LIMKs sont deux protéines kinases responsables de la régulation de la dynamique du cytosquelette d’actine et des microtubules. Leur dérégulation peut jouer un rôle prépondérant dans l’apparition de certaines maladies telles que la neurofibromatose de type 1, le cancer ou la sclérose latérale amyotrophique.Au cours de ce projet collaboratif, nous avons cherché à concevoir des inhibiteurs à la fois puissants et sélectifs des LIMKs en nous inspirant du composé le plus performant de l’époque développé par Lexicon Pharmaceuticals.Nous avons, dans un premier temps, travaillé sur la base hétérocyclique en remplaçant la pyrrolo[2,3-d]pyrimidine par différentes pyridopyrimidines et une triazolopyridopyrimidine. Cette dernière modification a ouvert la voie à un sujet de méthodologie autour du réarrangement de Dimroth. Nous avons ensuite modifié le cycle central pipérazine par une 3,6-dihydropyridine ou une pipéridine différemment substituée et avons fait varier la substitution au niveau de l’arylurée. Enfin, nous sommes revenus apporter quelques modifications structurales à la pyrrolo[2,3-d]pyrimidine de départ.Finalement, nous avons créé, à l’aide de méthodologies de synthèse efficaces, un large panel de composés originaux qui ont été testés in vitro et in cellulo sur nos cibles.Au travers de ce projet de chimie médicinale, nous avons pu approfondir les relations structure-activité afin de concevoir des inhibiteurs des LIMKs très prometteurs. / LIMKs are two protein kinases involved in regulating cytoskeleton and microtubule actin dynamics. Their deregulation can play a major role in the onset of several diseases such as neurofibromatosis type 1, cancer or amyotrophic lateral sclerosis.During this collaborative project, we have sought to design both potent and selective LIMKs inhibitors based on one of the most efficient compounds of the day developed by Lexicon Pharmaceuticals.We first worked on the heterocyclic base by replacing the pyrrolo[2,3-d]pyrimidine by different pyridopyrimidines and a triazolopyridopyrimidine. This last modification lead to a directed synthetic methodology study around the Dimroth rearrangement. We then modified the piperazine central ring with a differently substituted 3,6-dihydropyridine or piperidine and varied the substitution at the arylurea. Lastly, we made some further structural changes to the starting pyrrolo[2,3-d]pyrimidine.In conclusion, we have created, using effective synthetic methodology, a wide range of original compounds that have been tested in vitro and in cellulo on our targets.Through this medicinal chemistry project, we now have a better understanding of the structure-activity relationships needed in order to design very promising LIMK inhibitors.

Aims: To provide 12-month prevalence and disability burden estimates of a broad range of mental and neurological disorders in the European Union (EU) and to compare these findings to previous estimates. Referring to our previous 2005 review, improved up-to-date data for the enlarged EU on a broader range of disorders than previously covered are needed for basic, clinical and public health research and policy decisions and to inform about the estimated number of persons affected in the EU. Method: Stepwise multi-method approach, consisting of systematic literature reviews, reanalyses of existing data sets, national surveys and expert consultations. Studies and data from all member states of the European Union (EU-27) plus Switzerland, Iceland and Norway were included. Supplementary information about neurological disorders is provided, although methodological constraints prohibited the derivation of overall prevalence estimates for mental and neurological disorders. Disease burden was measured by disability adjusted life years (DALY). Results: Prevalence: It is estimated that each year 38.2% of the EU population suffers from a mental disorder. Adjusted for age and comorbidity, this corresponds to 164.8 million persons affected. Compared to 2005 (27.4%) this higher estimate is entirely due to the inclusion of 14 new disorders also covering childhood/adolescence as well as the elderly. The estimated higher number of persons affected (2011: 165 m vs. 2005: 82 m) is due to coverage of childhood and old age populations, new disorders and of new EU membership states. The most frequent disorders are anxiety disorders (14.0%), insomnia (7.0%), major depression (6.9%), somatoform (6.3%), alcohol and drug dependence (> 4%), ADHD (5%) in the young, and dementia (1–30%, depending on age). Except for substance use disorders and mental retardation, there were no substantial cultural or country variations. Although many sources, including national health insurance programs, reveal increases in sick leave, early retirement and treatment rates due to mental disorders, rates in the community have not increased with a few exceptions (i.e. dementia). There were also no consistent indications of improvements with regard to low treatment rates, delayed treatment provision and grossly inadequate treatment. Disability: Disorders of the brain and mental disorders in particular, contribute 26.6% of the total all cause burden, thus a greater proportion as compared to other regions of the world. The rank order of the most disabling diseases differs markedly by gender and age group; overall, the four most disabling single conditions were: depression, dementias, alcohol use disorders and stroke. Conclusion: In every year over a third of the total EU population suffers from mental disorders. The true size of “disorders of the brain” including neurological disorders is even considerably larger. Disorders of the brain are the largest contributor to the all cause morbidity burden as measured by DALY in the EU. No indications for increasing overall rates of mental disorders were found nor of improved care and treatment since 2005; less than one third of all cases receive any treatment, suggesting a considerable level of unmet needs. We conclude that the true size and burden of disorders of the brain in the EU was significantly underestimated in the past. Concerted priority action is needed at all levels, including substantially increased funding for basic, clinical and public health research in order to identify better strategies for improved prevention and treatment for disorders of the brain as the core health challenge of the 21st century.

Background: The spectrum of disorders of the brain is large, covering hundreds of disorders that are listed in either the mental or neurological disorder chapters of the established international diagnostic classification systems. These disorders have a high prevalence as well as short- and long-term impairments and disabilities. Therefore they are an emotional, financial and social burden to the patients, their families and their social network. In a 2005 landmark study, we estimated for the first time the annual cost of 12 major groups of disorders of the brain in Europe and gave a conservative estimate of €386 billion for the year 2004. This estimate was limited in scope and conservative due to the lack of sufficiently comprehensive epidemiological and/or economic data on several important diagnostic groups. We are now in a position to substantially improve and revise the 2004 estimates. In the present report we cover 19 major groups of disorders, 7 more than previously, of an increased range of age groups and more cost items. We therefore present much improved cost estimates. Our revised estimates also now include the new EU member states, and hence a population of 514 million people. Aims: To estimate the number of persons with defined disorders of the brain in Europe in 2010, the total cost per person related to each disease in terms of direct and indirect costs, and an estimate of the total cost per disorder and country. Methods: The best available estimates of the prevalence and cost per person for 19 groups of disorders of the brain (covering well over 100 specific disorders) were identified via a systematic review of the published literature. Together with the twelve disorders included in 2004, the following range of mental and neurologic groups of disorders is covered: addictive disorders, affective disorders, anxiety disorders, brain tumor, childhood and adolescent disorders (developmental disorders), dementia, eating disorders, epilepsy, mental retardation, migraine, multiple sclerosis, neuromuscular disorders, Parkinson's disease, personality disorders, psychotic disorders, sleep disorders, somatoform disorders, stroke, and traumatic brain injury. Epidemiologic panels were charged to complete the literature review for each disorder in order to estimate the 12-month prevalence, and health economic panels were charged to estimate best cost-estimates. A cost model was developed to combine the epidemiologic and economic data and estimate the total cost of each disorder in each of 30 European countries (EU27 + Iceland, Norway and Switzerland). The cost model was populated with national statistics from Eurostat to adjust all costs to 2010 values, converting all local currencies to Euro, imputing costs for countries where no data were available, and aggregating country estimates to purchasing power parity adjusted estimates for the total cost of disorders of the brain in Europe 2010. Results: The total cost of disorders of the brain was estimated at €798 billion in 2010. Direct costs constitute the majority of costs (37% direct healthcare costs and 23% direct non-medical costs) whereas the remaining 40% were indirect costs associated with patients' production losses. On average, the estimated cost per person with a disorder of the brain in Europe ranged between €285 for headache and €30,000 for neuromuscular disorders. The European per capita cost of disorders of the brain was €1550 on average but varied by country. The cost (in billion €PPP 2010) of the disorders of the brain included in this study was as follows: addiction: €65.7; anxiety disorders: €74.4; brain tumor: €5.2; child/adolescent disorders: €21.3; dementia: €105.2; eating disorders: €0.8; epilepsy: €13.8; headache: €43.5; mental retardation: €43.3; mood disorders: €113.4; multiple sclerosis: €14.6; neuromuscular disorders: €7.7; Parkinson's disease: €13.9; personality disorders: €27.3; psychotic disorders: €93.9; sleep disorders: €35.4; somatoform disorder: €21.2; stroke: €64.1; traumatic brain injury: €33.0. It should be noted that the revised estimate of those disorders included in the previous 2004 report constituted €477 billion, by and large confirming our previous study results after considering the inflation and population increase since 2004. Further, our results were consistent with administrative data on the health care expenditure in Europe, and comparable to previous studies on the cost of specific disorders in Europe. Our estimates were lower than comparable estimates from the US. Discussion: This study was based on the best currently available data in Europe and our model enabled extrapolation to countries where no data could be found. Still, the scarcity of data is an important source of uncertainty in our estimates and may imply over- or underestimations in some disorders and countries. Even though this review included many disorders, diagnoses, age groups and cost items that were omitted in 2004, there are still remaining disorders that could not be included due to limitations in the available data. We therefore consider our estimate of the total cost of the disorders of the brain in Europe to be conservative. In terms of the health economic burden outlined in this report, disorders of the brain likely constitute the number one economic challenge for European health care, now and in the future. Data presented in this report should be considered by all stakeholder groups, including policy makers, industry and patient advocacy groups, to reconsider the current science, research and public health agenda and define a coordinated plan of action of various levels to address the associated challenges. Recommendations: Political action is required in light of the present high cost of disorders of the brain. Funding of brain research must be increased; care for patients with brain disorders as well as teaching at medical schools and other health related educations must be quantitatively and qualitatively improved, including psychological treatments. The current move of the pharmaceutical industry away from brain related indications must be halted and reversed. Continued research into the cost of the many disorders not included in the present study is warranted. It is essential that not only the EU but also the national governments forcefully support these initiatives.

Submitted by Socorro Pontes (socorrop@ufersa.edu.br) on 2017-08-18T12:28:39Z No. of bitstreams: 1 SeverinoAGN_TESE.pdf: 2150050 bytes, checksum: 6442b9c49e9ff17a63707c19632e1884 (MD5) / Approved for entry into archive by Vanessa Christiane (referencia@ufersa.edu.br) on 2017-08-21T16:39:07Z (GMT) No. of bitstreams: 1 SeverinoAGN_TESE.pdf: 2150050 bytes, checksum: 6442b9c49e9ff17a63707c19632e1884 (MD5) / Approved for entry into archive by Vanessa Christiane (referencia@ufersa.edu.br) on 2017-08-21T16:39:22Z (GMT) No. of bitstreams: 1 SeverinoAGN_TESE.pdf: 2150050 bytes, checksum: 6442b9c49e9ff17a63707c19632e1884 (MD5) / Made available in DSpace on 2017-08-21T16:39:40Z (GMT). No. of bitstreams: 1 SeverinoAGN_TESE.pdf: 2150050 bytes, checksum: 6442b9c49e9ff17a63707c19632e1884 (MD5) Previous issue date: 2017-07-12 / The genus Marsdenia belongs to the Apocynaceae(Asclepiadoideae)family, are distributed worldwide and although several species of this genus are used in traditional Asian medicine for the treatment of rheumatic pain, inflammation, asthma, syphilis and cancer.Marsdenia megalantha is a rupicolous shrub with succulent roots of the semi-arid region of Brazil, is mentioned by farmers as the cause of intoxication in cattle, goats, sheep, pigs, equines and asinines. The clinical and pathological findings of the experimental administration of M. megalantha to sheep, goats, calf and swine are reported. Were dosed once orally with freshly chopped roots at dose of 25 g wet plant/kg bw; another sheep ad a pig were dosed with 10g wet plant/kg bw. Poisoning occurred in all of the animals except the three goats. Clinical signs of poisoning included tachycardia, opisthotonus, ruminal bloat, dyspnea, nystagmus, mydriasis, ataxia, and recumbence with paddling moviments. Pathological evaluation showed segmental laminar neuronal necrosis and spongiosis in the telencephalic cortex and degeneration of Purkinje cells. The picrate paper procedure detected no cyanide in the plant roots, but the reaction used for nitrate detection gave a strongly positive response. In a second experiment a dose of 10, 25 and 7 g / kg, respectively, was given to a cow, a goat and a sheep with calves of approximately 30 days. Aiming to assess whether the toxic principle, still unknown, passed through the milk and would be intoxicating the lactating animals. The administration lasted 5 days in the cow, 10 days in the sheep and only three days in the goat. And only the goat showed clinical signs of intoxication, no other animals nor their offspring showed any clinical signs. In conclusion, M. megalantha is a plant that produces acute intoxication characterized mainly by nervous disorders, the toxic principle or the toxic principles did not pass through the milk or passed in quantities insufficient to cause intoxication in the young, the pig was the species more sensitive to the goat The most resistant to intoxication, and producers of production animals should offer alternative foods during the dry season and early in the rainy season to avoid the occurrence of intoxication by this plant / As plantas do gênero Marsdenia, família Apocynaceae (Asclepiadoideae), apresentam distribuição mundial e apesar de diversas espécies deste gênero serem usadas na medicina tradicional asiática para o tratamento de dores reumáticas, inflamação, asma, sífilis e câncer. A Marsdenia megalantha que é um arbusto rupícola com raízes suculentas da região semiárida do Brasil é mencionada por prudutores rurais como a causa de intoxicação em bovinos, caprinos, ovinos, suínos, equino e asinino. São relatados os achados clínicos e patológicos da administração experimental de M. megalantha a ovinos, caprinos, bezerro e suíno. Foram administradas a três cabras, dois carneiros e um bezerro uma dose única por via oral de raízes recém-cortadas numa dose de 25 g de planta verde/kg de peso corporal; a outro carneiro e um suíno foram administradas a dose de 10 g/kg. A intoxicação ocorreu em todos os animais, exceto nas três cabras. Os sinais clínicos de intoxicação incluíram taquicardia, opistótono, timpanismo gasoso, dispneia, nistagmo, midríase, ataxia, andar rígido, decúbito e movimentos de pedalagem. A avaliação patológica mostrou necrose neuronal laminar segmentar, córtex telencefálico com aspecto espongiforme e degeneração de células de Purkinje. O procedimento com papel de picrato não detectou cianeto nas raízes das plantas, mas a reação utilizada para a detecção de nitratos deu uma resposta fortemente positiva. Em um segundo experimento foram administradas a uma vaca, uma cabra e a uma ovelha com crias de aproximadamente 30 dias, doses de 10, 25 e 7 g/Kg, respectivamente. Tendo como objetivo avaliar se o principio tóxico, ainda desconhecido, passava ou não pelo leite e se intoxicaria os animais lactantes. A administração durou 5 dias na vaca, 10 dias na ovelha e apenas três dias na cabra. E somente a cabra apresentou sinais clínicos de intoxicação, nenhum outro animal e nem suas crias apresentaram nenhum sinal clínico. Em conclusão, M. megalantha é uma planta que produz intoxicação aguda caracterizada principalmente por distúrbios nervosos, o princípio tóxico ou os princípios tóxicos não passaram pelo leite ou passaram em quantidades 10 insuficientes para causar intoxicação nas crias, o suíno foi a espécie mais sensível a e a cabra a mais resistente a intoxicação, e os produtores de animais de produção deveriam oferecer alimentos alternativos durante as estações de seca e início da estação das chuvas para evitar a ocorrência de intoxicação por esta planta / 2017-08-18

Abstract The speech and language abilities of preterm and low birthweight children were studied at the age of 8 in the northern Finland 1-year birth cohort for 1985 - 86. The language abilities of 42 8-year-old preterm children with birthweight < 1750 g were studied with four different language tests: the Illinois Test of Psycholinguistic Abilities (ITPA), the Token Test for Children (TTC), the Morphological Test for Finnish speaking children (MT) and the Peabody Picture Vocabulary Test (PPVT). Full-term control children with birthweight ≥ 2500 g (n = 42) from the same birth cohort matched individually with their preterm pairs for age, sex, twinship, mother's education, place of residence, birth order and family type were also studied. In addition, linguistic and motor abilities of low birthweight (LBW, < 2500 g) 8-year-old children (n = 279) were studied using parental (n = 8370, 90 %) and teacher (n = 8525, 92 %) evaluations by mailed questionnaire. The results showed that the 8-year-old preterm (< 1750 g) children scored significantly poorer than their controls in visual subtests measured by ITPA and that the poor performance in visual tests was associated with neonatal infections, continuous positive airway pressure (CPAP) and patent ductus arteriosus (PDA). In addition, the preterm children with minor neurodevelopmental dysfunction (MND) scored worst and differed significantly from their matched controls in verbal comprehension measured by TTC. They also differed significantly from other preterm groups, namely healthy preterm and preterm children with cerebral palsy (CP) in TTC. Periventricular leukomalasia (PVL) findings in magnetic resonance imaging (MRI) were not associated with the performance in the language ability tests. The parents evaluated the LBW (< 2500 g) children to have more problems in speech and language than the normal birth-weight (NBW, ≥ 2500 g) children. The LBW boys were the poorest in linguistic and motor skills compared with the NBW boys or any of the groups of girls. There was also a clear relationship between speech/linguistic and motor disabilities. Multivariate logistic regression analyses showed that the lower birthweight and some sociodemographic factors, for example mother's younger age (20 - 24y), having more than four children in the family, a reconstructed family, as well as hearing impairment and male gender were the most important determinants of poor speech and language abilities at 8 years of age, with and without adjustment for neonatal risk factor. Smallness for gestational age was also a risk factor for poor speech and language skills. Preterm birth was associated with poor skills only after removal of the neonatal risk factor from the model. Brain auditory evoked potential (BAEP) findings did not associate to poor language abilities of preterm children. To conclude, the preterm (< 1750 g) and the LBW children experienced speech and language disabilities at 8 years of age more than their full-term mates with NBW. Problems in speech production and especially in speech perception were more frequent among them both in clinical studies and parental evaluations.The visual problems were typical for preterm children (< 1750 g), which should be taken into account also in speech therapy. A closer and regular follow-up of language development in the preterm children with MND is important. Parental and teachers evaluations are useful in studying children's speech and language abilities. / Tiivistelmä Pohjoissuomalaisen vuoden 1985 - 86 syntymäkohortin ennenaikaisina ja pienipainoisina syntyneiden lasten puheen- ja kielenkehitystä tutkittiin heidän ollessaan 8-vuotiaita. Aluksi testattiin 42 ennenaikaisena ja alle 1750 g syntyessään painanutta 8-vuotiasta lasta sekä heidän 42 täysiaikaisina syntynyttä ja ≥ 2500 g painanutta kontrollipariaan neljällä kielellisellä testillä, nimittäin Illinois Test of Psycholinguistic Abilities -testillä (ITPA), Lasten Token testillä, Morfologiatestillä ja Peabody Picture Vocabulary Test nimisellä sanavarastotestillä (PPVT). Kontrollilapset valittiin samasta kohortista ja kaltaistettiin ennenaikaisina syntyneiden lasten kanssa iän, sukupuolen, kaksosuuden, äidin koulutuksen, asuinpaikan, syntymäjärjestyksen ja perhetyypin perusteella. Koko syntymäkohortin kaikkien pienipainoisina (LBW, < 2500 g) syntyneiden 8-vuotiaiden lasten (n=279) kielellisiä ja motorisia taitoja tutkittiin lisäksi vanhemmille (n = 8370, 90 %) ja opettajille (n = 8525, 92 %) osoitetun kyselyn perusteella. Tulokset osoittivat, että ennenaikaisina (< 1750 g) syntyneet lapset saivat merkitsevästi heikommat pisteet kuin heidän kontrollinsa ITPA:n visuaalisissa tehtävissä. Heikko visuaalinen suoriutuminen oli yhteydessä neonataalikauden infektioihin, ylipainehoitoon (CPAP) ja avoimeen valtimotiehyeen (PDA). Lisäksi ne ennenaikaisina syntyneet lapset, joilla oli lievää neurologista toiminnan häiriötä (MND) saivat puheen ymmärtämistä mittaavasta Token testistä heikommat pisteet kuin kontrollinsa. MND-lapset erosivat myös merkitsevästi muista ennenaikaisina syntyneistä lapsista, terveistä ja CP-vammaisista, Token testillä mitattuna. Periventrikulaarisen leukomalasian (PVL) löydökset aivojen magneettikuvauksessa (MRI) eivät olleet yhteydessä suoriutumiseen kielellisissä testeissä. Vanhempien arvioiden perusteella LBW lapsilla oli enemmän ongelmia puheessa ja kielessä kuin normaalipainoisina (NBW, ≥ 2500 g) syntyneillä kahdeksan vuoden iässä. LBW-pojat olivat heikompia kielellisissä ja motorisissa taidoissa kuin NBW-pojat tai kummatkaan tyttöjen ryhmät. Tutkimuksen perusteella puheen ja kielellisten taitojen sekä motoriikan välillä oli selvä yhteys. Monimuuttujaisen logistisen regressioanalyysin perusteella matala syntymäpaino sekä tietyt sosiodemografiset tekijät, kuten äidin nuori ikä (20 - 24 v.), perheen yli neljän menevä lapsimäärä, uusperhe sekä kuulovika ja poikasukupuoli olivat lasten keskeisimpiä heikkoon puheen- ja kielenkehitykseen liittyviä riskitekijöitä 8 vuoden iässä riippumatta siitä, oliko analyysissa mukana neonataalikauden riskitekijä vai ei. Pienipainoisuus raskauden kestoon nähden oli myös riski heikolle puheen ja kielen kehitykselle. Ennenaikaisuus oli yhteydessä heikkoon puheen ja kielen kehitykseen, kun neonataalikauden riskitekijä poissuljettiin analyysista. Aivorunkoaudiometrian (BAEP) löydökset puolestaan eivät olleet yhteydessä kielenkehityksen ongelmiin. Tutkimuksen johtopäätöksenä voidaan esittää, että ennenaikaisina (< 1750 g) syntyneillä ja LBW-lapsilla oli enemmän ongelmia kuin täysiaikaisina syntyneillä NBW-lapsilla puheen- ja kielenkehityksessään 8 vuoden iässä. Ongelmat puheen tuotossa ja erityisesti vastaanotossa olivat heillä yleisempiä sekä kliinisen tutkimuksen että vanhempien arvion perusteella. Visuaalisen hahmottamisen vaikeudet olivat tyypillisiä ennenaikaisina (< 1750 g) syntyneille lapsille, mikä olisi hyvä huomioida myös puheterapiassa. Tutkimuksen perusteella ennenaikaisina syntyneiden MND-lasten kielenkehityksen tarkka ja säännöllinen seuranta on tärkeää. Vanhempien ja opettajien arviot ovat hyödyllinen lisä lasten puheen- ja kielenkehityksen tutkimuksessa. / Čoahkkáigeassu Davvisuopmelaš jagi 1985-86 riegadankohortta ovdaláigge ja menddo geahpasin riegádan mánáid hupman- ja giellaovdaneapmi dutkojuvvui go mánát ledje 8-jahkáččat. Álggos testejuvvojedje 42 riegádettiin vuollái 1750 g deaddán 8-jahkásaš máná ja sin 42 dievasáigge šaddan ja ≥2500g deaddán kontrollapára njeljiin giellateasttain, namalassii ITP:ain (Illinois Test of Psycolinguistic Abilities), Mánáid Toke-teasttain, Morfologiijateasttain ja Peabody Picture Vocabulary Test-sátnerádjoteasttain (= PPTV). Kontrollapárat válljejuvvojedje seamma kohorttas ja dahkkojuvvojedje seammaláganin čuovvovaš áššiid ektui: ahki, sohkabealli,jumešvuohta,eatni skuvlejupmi,orrunbáiki,riegádanortnet ja bearaštiipa. Riegádankohortta menddo geahpasin (< 2500) riegádan 8-jahkásaš mánáid (n = 279) gielalaš ja motora dáiddut dutkojuvvojedje dasa lassin váhnemiid ja oahpaheaddjiid árvvoštallamiid vuođul. Mánáid váhnemiin 8370 (90%) ja oahpaheaddjiin 8525 (92%) vástidedje jearahallamii. Bohtosat čájehedje, ahte ovdaláigge riedágan mánát ožžo statistihkalaččat mearkkašahtti heajut čuoggaid go sin kontrollapárat ITPA visuála bargguin. Heajos visuála návccain lei oktavuohta neonatála-áiggi infekšuvnnaide, alladeaddodikšui (CPAP) ja rabas váibmosutnii (PDA). Dasa lassin ovdaláigge riegádan mánát, geain ledje muhtun veardde neurologalaš doaibmanváttut(MND) ožžo Toke-teasttas, mainna mihtidit hupmama ipmirdeapmi,heajut čuoggáid go sin kontrollapárat. MND-mánát sierranedje maiddái mearkkašahtti veardde Toke-teasttas eará ovdaláigge riegádan mánáin, sihke dearvasiin ja CP-váttogiin. Periventikuláralaš leukomasiija (PVL) gávdnosiin ii lean oktavuohta gielalaš teasttain birgemii. Periventikuláralaš leukomasiija (PVL) gávdnosiin magnehtagovvideamis(MRI) ii lean oktavuohta gielalaš teasttain birgemii. Váhnemiid árvvoštallama mielde menddo geahpasin riegádan mánáin ledje eambbo váttisvuođat hupmamis go normáladeattogin riegádan mánáin. Menddo geahpasin riegádan bártnit ledje heajubut gielalaš ja ja motora dáidduid ektui go normáladeattogin riegádan bártnit dahje goabbáge nieddaid joavkkuin. Dutkamuša vuođul hupmama ja gielalaš dáidduid ja motoriikka gaskkas lea čielga oktavuohta. Logistihkalas regreššuvdna-analiissa,mas ledje máŋga rievdi, vuođul menddo geahppa riegádandeaddu ja dihto sosiodemográfalaš dahkkit, dego eatni ahki (20-24 j.), mánáid lohku > 4 bearrašis, ođđabearaš ja lossa gullu ja bárdnesohkabealli ledje mánáid deaháleamos heajos hupmama ja giela ovdaneami einnosteaddjit 8 jagi agis, fuolakeahttá das, leigo analiissas mielde neonatála-áiggi várradahkki vai ii. Menddo geahppa riegádandeaddu ohkeagi ektui lasihii maiddái vára ahte mánná hupmagoahtá heajut ja su giella ovdana funet. Ovdaláigge riegádeamis lei oktavuohta heajos hupmama ja giela ovdaneapmái, go neonatála-áigge várradahkki ii váldojuvvon vuhtii analiissas. BAEP-gávdnosiin ii lean fas lean oktavuohta giela heajos ovdaneapmái. Dutkamuša jurddaboađusin sáhttá buktit ovdan,ahte ovdaláigge ja menddo geahpasin riegádan mánáin ledje 8- jahkásažžan eambbo váttisvuođat hupmama ja giela ovdaneamis go ollesáigge ja normáladeattogin riegádan mánáin. Maiddái hupmama ipmirdeamis ledje eambbo váttisvuođat. Heajos visuála návccat ledje sidjiide mihtilmaččat ja dan galggašii váldit vuhtii maid hupmanterapiijas.Dutkamuša vuođul MND-mánáid giellaovdaneami dárkilit ja regulára čuovvun lea deahálaš. Váhnemiid ja oahpaheaddjiid árvvoštallamat sáhttet leat ávkkalaččat mánáid hupmama ja giela ovdameami dutkamis.

Aims: To provide 12-month prevalence and disability burden estimates of a broad range of mental and neurological disorders in the European Union (EU) and to compare these findings to previous estimates. Referring to our previous 2005 review, improved up-to-date data for the enlarged EU on a broader range of disorders than previously covered are needed for basic, clinical and public health research and policy decisions and to inform about the estimated number of persons affected in the EU. Method: Stepwise multi-method approach, consisting of systematic literature reviews, reanalyses of existing data sets, national surveys and expert consultations. Studies and data from all member states of the European Union (EU-27) plus Switzerland, Iceland and Norway were included. Supplementary information about neurological disorders is provided, although methodological constraints prohibited the derivation of overall prevalence estimates for mental and neurological disorders. Disease burden was measured by disability adjusted life years (DALY). Results: Prevalence: It is estimated that each year 38.2% of the EU population suffers from a mental disorder. Adjusted for age and comorbidity, this corresponds to 164.8 million persons affected. Compared to 2005 (27.4%) this higher estimate is entirely due to the inclusion of 14 new disorders also covering childhood/adolescence as well as the elderly. The estimated higher number of persons affected (2011: 165 m vs. 2005: 82 m) is due to coverage of childhood and old age populations, new disorders and of new EU membership states. The most frequent disorders are anxiety disorders (14.0%), insomnia (7.0%), major depression (6.9%), somatoform (6.3%), alcohol and drug dependence (> 4%), ADHD (5%) in the young, and dementia (1–30%, depending on age). Except for substance use disorders and mental retardation, there were no substantial cultural or country variations. Although many sources, including national health insurance programs, reveal increases in sick leave, early retirement and treatment rates due to mental disorders, rates in the community have not increased with a few exceptions (i.e. dementia). There were also no consistent indications of improvements with regard to low treatment rates, delayed treatment provision and grossly inadequate treatment. Disability: Disorders of the brain and mental disorders in particular, contribute 26.6% of the total all cause burden, thus a greater proportion as compared to other regions of the world. The rank order of the most disabling diseases differs markedly by gender and age group; overall, the four most disabling single conditions were: depression, dementias, alcohol use disorders and stroke. Conclusion: In every year over a third of the total EU population suffers from mental disorders. The true size of “disorders of the brain” including neurological disorders is even considerably larger. Disorders of the brain are the largest contributor to the all cause morbidity burden as measured by DALY in the EU. No indications for increasing overall rates of mental disorders were found nor of improved care and treatment since 2005; less than one third of all cases receive any treatment, suggesting a considerable level of unmet needs. We conclude that the true size and burden of disorders of the brain in the EU was significantly underestimated in the past. Concerted priority action is needed at all levels, including substantially increased funding for basic, clinical and public health research in order to identify better strategies for improved prevention and treatment for disorders of the brain as the core health challenge of the 21st century.

Background: The spectrum of disorders of the brain is large, covering hundreds of disorders that are listed in either the mental or neurological disorder chapters of the established international diagnostic classification systems. These disorders have a high prevalence as well as short- and long-term impairments and disabilities. Therefore they are an emotional, financial and social burden to the patients, their families and their social network. In a 2005 landmark study, we estimated for the first time the annual cost of 12 major groups of disorders of the brain in Europe and gave a conservative estimate of €386 billion for the year 2004. This estimate was limited in scope and conservative due to the lack of sufficiently comprehensive epidemiological and/or economic data on several important diagnostic groups. We are now in a position to substantially improve and revise the 2004 estimates. In the present report we cover 19 major groups of disorders, 7 more than previously, of an increased range of age groups and more cost items. We therefore present much improved cost estimates. Our revised estimates also now include the new EU member states, and hence a population of 514 million people. Aims: To estimate the number of persons with defined disorders of the brain in Europe in 2010, the total cost per person related to each disease in terms of direct and indirect costs, and an estimate of the total cost per disorder and country. Methods: The best available estimates of the prevalence and cost per person for 19 groups of disorders of the brain (covering well over 100 specific disorders) were identified via a systematic review of the published literature. Together with the twelve disorders included in 2004, the following range of mental and neurologic groups of disorders is covered: addictive disorders, affective disorders, anxiety disorders, brain tumor, childhood and adolescent disorders (developmental disorders), dementia, eating disorders, epilepsy, mental retardation, migraine, multiple sclerosis, neuromuscular disorders, Parkinson's disease, personality disorders, psychotic disorders, sleep disorders, somatoform disorders, stroke, and traumatic brain injury. Epidemiologic panels were charged to complete the literature review for each disorder in order to estimate the 12-month prevalence, and health economic panels were charged to estimate best cost-estimates. A cost model was developed to combine the epidemiologic and economic data and estimate the total cost of each disorder in each of 30 European countries (EU27 + Iceland, Norway and Switzerland). The cost model was populated with national statistics from Eurostat to adjust all costs to 2010 values, converting all local currencies to Euro, imputing costs for countries where no data were available, and aggregating country estimates to purchasing power parity adjusted estimates for the total cost of disorders of the brain in Europe 2010. Results: The total cost of disorders of the brain was estimated at €798 billion in 2010. Direct costs constitute the majority of costs (37% direct healthcare costs and 23% direct non-medical costs) whereas the remaining 40% were indirect costs associated with patients' production losses. On average, the estimated cost per person with a disorder of the brain in Europe ranged between €285 for headache and €30,000 for neuromuscular disorders. The European per capita cost of disorders of the brain was €1550 on average but varied by country. The cost (in billion €PPP 2010) of the disorders of the brain included in this study was as follows: addiction: €65.7; anxiety disorders: €74.4; brain tumor: €5.2; child/adolescent disorders: €21.3; dementia: €105.2; eating disorders: €0.8; epilepsy: €13.8; headache: €43.5; mental retardation: €43.3; mood disorders: €113.4; multiple sclerosis: €14.6; neuromuscular disorders: €7.7; Parkinson's disease: €13.9; personality disorders: €27.3; psychotic disorders: €93.9; sleep disorders: €35.4; somatoform disorder: €21.2; stroke: €64.1; traumatic brain injury: €33.0. It should be noted that the revised estimate of those disorders included in the previous 2004 report constituted €477 billion, by and large confirming our previous study results after considering the inflation and population increase since 2004. Further, our results were consistent with administrative data on the health care expenditure in Europe, and comparable to previous studies on the cost of specific disorders in Europe. Our estimates were lower than comparable estimates from the US. Discussion: This study was based on the best currently available data in Europe and our model enabled extrapolation to countries where no data could be found. Still, the scarcity of data is an important source of uncertainty in our estimates and may imply over- or underestimations in some disorders and countries. Even though this review included many disorders, diagnoses, age groups and cost items that were omitted in 2004, there are still remaining disorders that could not be included due to limitations in the available data. We therefore consider our estimate of the total cost of the disorders of the brain in Europe to be conservative. In terms of the health economic burden outlined in this report, disorders of the brain likely constitute the number one economic challenge for European health care, now and in the future. Data presented in this report should be considered by all stakeholder groups, including policy makers, industry and patient advocacy groups, to reconsider the current science, research and public health agenda and define a coordinated plan of action of various levels to address the associated challenges. Recommendations: Political action is required in light of the present high cost of disorders of the brain. Funding of brain research must be increased; care for patients with brain disorders as well as teaching at medical schools and other health related educations must be quantitatively and qualitatively improved, including psychological treatments. The current move of the pharmaceutical industry away from brain related indications must be halted and reversed. Continued research into the cost of the many disorders not included in the present study is warranted. It is essential that not only the EU but also the national governments forcefully support these initiatives.

The human genome is constantly under the attack by various damaging agents, leading to the breakage of one or both strands of DNA that might interfere with RNA processing. Importantly, our cells have evolved diverse mechanisms to rapidly repair various DNA lesions, highlighting the importance of genetic integrity. Defects in DNA repair and/or RNA metabolism can lead to a variety of human hereditary diseases, with pathologies including growth and developmental defects, immunodeficiency, predisposition to cancer, and neurodegeneration. Mutations in the BRAT1 (BRCA1-associated ATM activator-1) protein have been associated with neurological disorders characterized by heterogenous phenotypes with varying levels of clinical severity ranging from microcephaly, hypertonia, epilepsy, seizures, and early death in the first two years of life to mild cerebellar atrophy and ataxia. Previously, BRAT1 protein has been implicated in the cellular response to DNA double-strand breaks and ATM signalling. However, the exact mechanism/s by which mutations in BRAT1 gene trigger neurological disorders are largely unknown. Recently, we have identified a homozygous missense c.185T>A (p.Val62Glu) variant in BRAT1 that markedly reduced the level of BRAT1 protein in patient-derived cell lines. Surprisingly, our data show that...

No description available.

Title: The Use of Vibration in Sports and Health Care Objectives: The aim of this study is to confirm or refute established hypotheses. Hypotheses: 1. The use of vibration loading improves muscle strength. 2. The use of vibration loading improves bone mineral density. 3. The use of vibration loading can influence balance. Methods: This diploma thesis is elaborated as search form. It is based on exploration of available literary sources, clinical trials accessible through electronic databases of medical and sports, and library catalogs. The resources from sport, physiology, biomechanics, and various medical disciplines (osteology, physiotherapy, kinesiology) were used also. Results: Due to retrieval process of whole body vibration training it was found out that this method can improve muscle strength, bone mineral density, balance and mobility. The effect depends on chosen parameters of whole-body vibrations. Under certain conditions whole-body vibration training could represent an alternative or a supplement to conventional training in order to increase muscle strength and bone mineral density or improve balance and mobility of elderly. The selection of right vibration parameters could support ordinary physical therapy of some neurological disorders. Keywords: vibration, whole-body vibration...